CA3188131A1 - Polycyclic amines for opioid receptor modulation - Google Patents

Polycyclic amines for opioid receptor modulation

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Publication number
CA3188131A1
CA3188131A1 CA3188131A CA3188131A CA3188131A1 CA 3188131 A1 CA3188131 A1 CA 3188131A1 CA 3188131 A CA3188131 A CA 3188131A CA 3188131 A CA3188131 A CA 3188131A CA 3188131 A1 CA3188131 A1 CA 3188131A1
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CA
Canada
Prior art keywords
ethyl
propan
pyrrolidin
citrate
fluorothiophen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CA3188131A
Other languages
French (fr)
Inventor
Xiaodong Wang
Baizhi LI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ecstasy LLC
Original Assignee
Ecstasy LLC
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Filing date
Publication date
Application filed by Ecstasy LLC filed Critical Ecstasy LLC
Publication of CA3188131A1 publication Critical patent/CA3188131A1/en
Pending legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract

The present invention discloses a number of polycyclic amines that are useful as opioid receptor modulators. The compounds of the invention are useful in both therapeutic and diagnostic methods, including for treating pain, neurological disorders, cardiac disorders, bowel disorders, drug and alcohol addiction, drug overdose, urinary disorders, respiratory disorders, sexual dysfunction, psoriasis, graft rejection or cancer.

Description

2 POLYCYCLIC AMINES FOR OPIOID RECEPTOR MODULATION
BACKGROUND
There is a continuing need for new opioid receptors modulators for the management of pain with reduced or fewer side effects. There is also a continuing need for new opioid receptors modulators for the treatment migraine, depression, cognitive disorders, Parkinson's disease, locomotor disfunction, pruritus, diarrhea, irritable bowel syndrome and gastro-intestinal disorders, bladder dysfunctions, overactive bladder, urinary incontinence, neurogenic bladder, interstitial cystitis, drug addiction, alcohol addiction, drug overdose, premature ejaculation, cough, lung edema, cardiac disorders, cardioprotection, and respiratory depression, and as immunomodulatory and anti-tumor agents. A number of such opioid receptor modulators are disclosed in US
Pat. No. 10,676,456 (incorporated by reference). Some additional new compounds are shown below.
SUMMARY
The present invention provides polycyclic amines, prodrugs and pharmaceutically acceptable salts thereof ("compounds of the invention"), which are useful in the treatment of diseases through the modulation of opioid receptors; similar to the compounds and their uses disclosed in US Pat. No. 10,676,456. The process of making the compounds listed below are disclosed in or similar to processes of making compounds disclosed in US Pat. No. 10,676,456.
The compounds of the invention are useful for preventing or treating a disease or condition selected from the group consisting of cardioprotection, cardiac disorders, analgesia, functional pain, inflammatory pain, peripherally mediated and neuropathic pain, non-somatic pain, arthritis, mental illness, cognitive disorders, depression, Parkinson's disease, locomotor disfunction, urogenital tract disorders, bladder dysfunction, overactive bladder, urinary incontinence, neurogenic bladder, psoriasis, pruritus, emesis, acne, skin lesions, non-ulcerogenic dyspepisa, gastro-intestinal disorders, functional bowel disease, diarrhea, inflammatory bowel disease, irritable bowel syndrome, interstitial cystitis, sexual dysfunctions, drug addiction, alcohol addiction, drug overdose, premature ejaculation, asthma, cough, lung edema, disorders of respiratory function, respiratory depression, functional distension, and disorders of motility or secretion. These compounds are also useful for immunomodulation, inhibiting or preventing organ or skin graft rejection, or treating tumors or cancer. All such treatment involves administering, to a patient, an effective amount of one or more of the compounds of the invention.
The present invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of the compounds of the invention.
These and other aspects and embodiments of the invention will be apparent from the detailed description that follows.
DETAILED DESCRIPTION
Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or double bonds in their structure. The compounds of the invention and their pharmaceutical acceptable salts may therefore exit as single stereoisomers, racemates, and as mixtures of enantiomers, diastereomers and geometric isomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the invention. Absolute configuration of certain carbon atoms within the compounds, if known, are indicated by the appropriate absolute descriptors R or S.
The compounds of the invention may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedure. The racemic compounds of the invention may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid.
Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of the invention involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation.
These methods will advantageously employ enantiomerically pure starting materials.
The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (.s up .3 H), iodine-125 (.s up .125I) or carbon-14 (14C). All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the present invention.
"Therapeutic" as used herein, includes prevention, treatment and/or prophylaxis for humans as well as other animals.
"Pharmaceutically or therapeutically effective dose or amount" refers to a dosage level sufficient to induce a desired biological result. That result may be the alleviation
3 of the signs, symptoms or causes of a disease or any other alteration of a biological system that is desired. The precise dosage will vary according to a variety of factors, including but not limited to the age and size of the subject, the disease and the treatment being effected.
A "host" or "patient" or "subject" is a living mammal, human or animal, for whom therapy is desired. The "host," "patient" or "subject" generally refers to the recipient of the therapy to be practiced according to the method of the invention. It should be noted that the invention described herein may be used for veterinary as well as human applications and that the term "host" should not be construed in a limiting manner. In the case of veterinary applications, the dosage ranges can be determined as described below, taking into account the body weight of the animal.
As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or a state government or listed in the U.S.
Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered and includes, but is not limited to such sterile liquids as water and oils.
The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
When compounds of the invention contain relatively basic functionalities, acid
4 addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
Other examples of pharmaceutically acceptable salts of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, calcium, magnesium), ammonium and NR'4 (wherein R is Ci-C4 alkyl). Pharmaceutically acceptable salts of the invention having an amino group include salts of: organic carboxylic acids such as acetic, lactic, tartaric, malic, lactobionic, fumaric, and succinic acids;
organic sulfonic acids such as methanesulfonic, ethanesulfonic, isethionic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of the invention having a hydroxyl group consist of the anion of such compounds in combination with a suitable cation such as Nat, NH4, or NR'4 , (wherein R is for example a Ci-C4 group).
The neutral forms of the compounds of the invention are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound of the invention. Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.

A "pharmaceutical composition" is a formulation comprising the disclosed compounds in a form suitable for administration to a subject. A pharmaceutical composition of the invention is preferably formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, oral and parenteral, e.g., intravenous, intradermal, subcutaneous, inhalation, topical, transdermal, transmucosal, and rectal administration.
The compounds of the invention can combine with an exogenous receptor or be used as complexing compounds, and may be used for binding with an opioid receptor.
Further, the compounds may be used as a conjugate in an agonist/antagonist pair that is employed for transductional assay of neurotransmitter function in appertaining cellular or differentiated tissue systems, as well as for receptor assay, differential binding, and specificity applications for cellular, histological, and corporeal monitoring and assessment purposes.
The compounds of the invention can be administered for therapeutic intervention in a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier. The invention contemplates the use of any means and/or of modality of administration of the compositions of the invention.
The compounds of the invention include their physiologically functional derivatives.
"Physiologically functional derivative" includes a pharmaceutically acceptable salt, ether, ester or salt of an ether or ester of the compounds of the invention or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of the invention or an active metabolite or residue thereof. Phenolic Ci-C6 alkyl ethers are a sub-class of physiologically functional derivatives of the compounds of the invention.
The compounds of the invention when used in pharmaceutical or diagnostic applications preferably are prepared in a racemic mixture or an essentially pure enantiomer form, with an enantiopurity of at least 90% enantiomeric excess (EE), preferably at least 95% EE, more preferably at least 98% EE, and most preferably at least 99% EE. Enantiomeric excess values provide a quantitative measure of the excess of the percentage amount of a major isomer over the percentage amount of a minor isomer which is present therewith, and may be readily determined by suitable methods well-known and established in the art, as for example chiral high pressure liquid chromatography (HPLC), chiral gas chromatography (GC), nuclear magnetic resonance (NMR) using chiral shift reagents, etc.
Subjects to be treated by administration of the compounds of the invention are preferably human subjects, but also include non-human mammals and other animals (e.g., bird, dog, cat, cow, horse).
Depending on the specific condition to be treated, subjects may be administered compounds of the invention at any suitable therapeutically effective and safe dosage, as may readily be determined within the skill of the art, and without undue experimentation, with extrapolation from the animal dosages set forth herein in the examples. In in vitro tests for agonist/antagonist activity, such as receptor binding affinity tests, and inhibition of electrically stimulated muscle twitch tests, compounds of the invention exhibit potency.
In general, while the effective dosage of compounds of the invention for therapeutic use may be widely varied in the broad practice of the invention, depending on the specific application, condition, or disease state involved, as readily determinable within the skill of the art, suitable therapeutic doses of the compounds of the invention, for each of the appertaining compositions described herein, and for achievement of therapeutic benefit in treatment of each of the conditions described herein, will be in the range of 10 micrograms (j.tg) to 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in the range of 50 jig to 75 mg per kilogram body weight per day, and most preferably in the range of 100ug to 50 mg per kilogram body weight per day. The desired dose is preferably presented as one, two, three, four, five, six, or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing from lOug to 1000 mg, preferably from 50ug to 500 mg, more preferably from 50ug to 250 mg, and most preferably from 50ug to 10 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.
The mode of administration and dosage forms will affect the therapeutic amounts of the compounds which are desirable and efficacious for the given treatment application.
For example, orally administered dosages typically are at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods, for the same active ingredient. In oral administration, dosage levels for delta receptor binding compounds of the invention may be on the order of 5-200 mg/70 kg body weight/day. In tablet dosage forms, typical active agent dose levels are on the order of 10-100 mg per tablet.
The compounds of the invention may be administered per se as well as in the form of pharmaceutically acceptable esters, salts, and ethers, as well as other physiologically functional derivatives of such compounds.
The present invention also contemplates pharmaceutical compositions, both for veterinary and for human medical use, which comprise as the active agent one or more compound(s) of the invention.

In such pharmaceutical compositions, the active agent preferably is utilized together with one or more pharmaceutically acceptable carrier(s) therefor and optionally any other therapeutic ingredients. The carrier(s) preferably are compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The active agent is preferably in a pharmaceutically acceptable amount effective to achieve the desired pharmacological effect.
The formulations include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, topical, sub-lingual, mucosal, transdermal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, and intra-uterine administration.
Formulations suitable for oral administration are preferred.
When the active agent is utilized in a formulation comprising a liquid solution, the formulation advantageously may be administered parenterally. When the active agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.
When the active agent is utilized directly in the form of a powdered solid, the active agent may be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.
In some applications, it may be advantageous to utilize the active agent in a "vectorized" form, such as by encapsulation of the active agent in a liposome or other encapsulant medium, or by fixation of the active agent, e.g., by covalent bonding, chelation, or associative coordination, on a suitable biomolecule, such as those selected from proteins, lipoproteins, glycoproteins, and polysaccharides.
The formulations comprising the compounds of the invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the compound(s) into association with a carrier that constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the active compound(s) into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules;
or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert compound, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
A syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.
Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.
Nasal spray formulations comprise purified aqueous solutions of the active compounds with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acids.
Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.
Topical formulations comprise the active compound dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.

Transdermal formulations may be prepared by incorporating the active agent in a thixotropic or gelatinous carrier such as a cellulosic medium, e.g., methyl cellulose or hydroxyethyl cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with the skin of a wearer.
In addition to the aforementioned ingredients, formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.
The disease state or physiological condition involved in such therapeutic intervention may be of any type or kind noted above, e.g., centrally mediated disorders;
pain, depression, drug addiction, and drug dependence, alcohol addiction; and peripherally mediated neuropathic pain, cough, lung edema, gastro-intestinal disorders, arthritis, psoriasis, asthma, inflammatory bowel disease, disorders of respiratory function, functional bowel disease, irritable bowel syndrome, diarrhea, functional distension, pain (e.g., functional pain, trauma pain, etc.), non-ulcerogenic dyspepsia, urogenital tract disorders, premature ejaculation, overactive bladder, urinary incontinence, organ transplant rejection, skin graft rejection, cardiac disorders, cardioprotection, emesis, acne and skin lesions.
The compounds of the present invention may be readily synthesized within the skill of the art and in view of the illustrative synthesis examples hereinafter set forth.
The invention is further illustrated by the following non-limiting preparation schemes and other examples.
PREPARATION OF OPIOID RECEPTOR MODULATORS
The following exemplary schemes illustrate methods of preparing the compounds of the invention, wherein the compounds of the invention have a structure according to Formula I, and include pharmaceutically acceptable salts and other derivatives of this structure:

A
(R2)m (R5)M
W (R6)m (R)4m I(G)'R3 R-. In Z
(Formula I) wherein:
A includes substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and arylalkyl;
Y includes substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl;
Q includes: substituted or unsubstituted: aryl, heteroaryl, and null;
W includes substituted or unsubstituted, saturated or unsaturated: (i) 4- to 8-membered heterocyclic rings including an N-substituent as an atom of the ring; and (ii) bicyclic or heterobicyclic fused rings wherein each ring has 4- to 10- members, and wherein at least one of the rings includes an N-substituent as an atom of the ring;
G includes substituted or unsubstituted alkyl or an N atom;
Z includes substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and null;
If Z is null then T is null, but if Z is not null, T is selected from: (i) the moieties H, OH, NH2, NO2, -SO2NH2, halogen, (ii) substituted or unsubstituted: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
n is an integer from 1-4 when G is alkyl and is 1 when G is an N atom;

R' and R3 are members independently selected from H and substituted or unsubstituted:
alkyl, heteroalkyl, 3- to 7- membered cycloalkyl, 3- to 7- membered heterocycloalkyl, aryl, and heteroaryl;
m is an integer from 0-8 and can be same or different for each of R2, R4, R5 and R6, and wherein R2, R4, R5 and R6 are each independently selected from H and substituted or unsubstituted: alkyl, heteroalkyl, 3- to 7- membered cycloalkyl, 3- to 7-membered heterocycloalkyl, and where m is greater than 1 for any of R2, R4, R5 and R6, each member in such a multi-member R2, R4, R5 and R6 chain can be the same or different;
and further provided that the total number of R2, R4, R5 and R6 having an m value greater than 0 is always less than or equal to the number of W ring positions available for covalent bonding; and R' and R3, or le or R3 and Z, or R2 and A, or R2 and Y together with groups to which they may be joined, optionally form a substituted or unsubstituted 3- to 7-membered ring.
Scheme 1 Compounds where "A" of Formula I is an alkyl or heteroalkyl moiety are synthesized as illustrated in Scheme 1. The synthesis of compounds 1-6 is exemplified.

;.R. .10."--`>.:(8=:'2 , ,.. , UAIth, c \ 1 R 1,4 w ,1, ----------N- R.147 " -1 W R, ____ 1 ir -N 2. KA
i5oc-= µBat (.30(::
1-1 I -2a. 1.-$

..11 R 0 .--..
3., ._:.õ4- -,, "0 =-=>4:-..õ
if = '. t_t: .." tl W= 1 ____ t. Ri...i.
\ l'A = )\-õ,õ.....,M=s k=,,,.,44,_,R, 0, RHikstR, .=,,.\'' R., .k. , I -5k:t PH
EtC10C ...1., ..R, EtO0C ,....1, , / ,R3 e" ,\
1-1 ____________ IN I rz- ______ j ,14 w ) .i. t -0. ,ot,, at4 0 = '\.___,-Ni Z.
1-2b 1-'2c . k 1-2d wherein for Scheme I above, X is selected from: Cl, Br, I, p-toluenesulfonyl (Tos), methanesulfonyl (Ms) and trifluoromethanesulfonyl (Tf).
In Scheme I, a substituted cyclic ester 1-1 is deprotonated in the presence of a strong base, such as LDA, LHMDS, or the like, followed by alkylation to produce 1-2a.

Reduction of 1-2a followed by alkylation gives the ether 1-4. Deprotection of the Boc group of 1-4 is carried out in the presence of an acid, such as TFA, HC1 orthe like.
Reductive amination of 1-5 with a suitable aldehyde or ketone 1-5a or alkylation of 1-5 with 1-5b under basic conditions gives 1-6. The compounds with different moieties from le are exemplified by the synthesis of intermediates such as 1-2b, 1-2c, or 1-2d. Reaction of 1-1 with a suitable ketone or aldehyde 1-7 gives the intermediate 1-2b. Activation of the hydroxyl group of 1-2b using MsC1 followed by the elimination in the presence of bases, such as DBU or the like, produces the unsaturated intermediates 1-2c. Hydrogenation of 1-2c gives the intermediate 1-2d.
Scheme 2 Compounds where "A" of Formula I is a cyclic alkyl or cyclic heteroalkyl moiety are synthesized as illustrated in Scheme 2. The synthesis of compounds 2-6 is used as an example.

HZ-3 R2 HO¨' R2 R4 0 R2 [0] R3MgBr R4X
Ri W ¨1" R1 W N, ¨1' R1(r)1, ¨jbase ' R1 W Ns Ns Boc Boc Boc Boc R6 f..---...x 2 R6 f.--xR6 0-7 \¨
1 . RCM 0 H+
¨'' ¨' W

2. [H] R1-\) R1W t Rt1 N, NH N R7 Boc 'C\

HO..Pi-L
Pr ,L, L
0 R2 02-1aMg Br R2 Ns ______________________ ..- R1 w N,Boc deprotection HO
____________________________________________ 0- Ri W ¨0- 2-4 N
Boc µBoc 2-1 2-7 zr NN
R9 ,h.. R9 6s0 Xµ'µ
rL,MgBr ¨5_ Rio Rio L
Ri i HO
2-lb Ns Boc L: alkyl or heteroalkyl linkers; Pr: protection groups Oxidation of 1-3 to 2-1 is carried out by Swern oxidation or other oxidants, such as Dess-Martin Periodiane or the like. Grignard reaction of aldehyde 2-1 with an unsaturated or a saturated Grignard reagent, followed by alkylation with an unsaturated or a saturated alkylating reagent under basic condition gives 2-3.

Ring-closing metathesis (RCM) of 2-3 with a catalyst, such as Grubbs ruthenium-carbene complexes or the like, yields an unsaturated oxygen-containing heterocyclic 2-4 or a saturated oxygen-containing heterocyclic 2-4 after hydrogenation. Alternatively, the synthesis of 2-4 is achieved by a Grignard reaction of 2-1 with 2-la or 2-1b, followed by either deprotection of the intermediate 2-7 or hydroboration of double bond of the intermediate 2-9 to give the corresponding diol 2-8. The diol 2-8 is converted to 2-4 by intramolecular cyclization under Mitsunobu reaction condition or displacement of the corresponding mesylates, tosylates, or the like.
Finally, the synthesis of 2-6 from 2-4 is achieved using the same methodology as the conversion of 1-4 to 1-6 in Scheme 1.
Scheme 3 Compounds where "A" of Formula I is a heteroaryl moiety are synthesized as illustrated in Scheme 3 and exemplified by the synthesis of 3-8.

Ri w RiMg Br Ri N w ____________________ TMSCN R1 w _CII) Ns N, Heteroaryl R2 'Boc Boc Boc N,Boc I

Base R1 Base ¨v- R1-ei N, R2X Ns Boc Boc Heteroaryl R2 Heteroaryl R2 -I.- R1 W N R4 NH
Do izpX.
..5 ..6 / NH
I\1 Cc I2 OHC R2 R7¨t.........i\R2 N
R1_ W ¨..- RI-CI) ¨,.- R1 W , 'Boc N,Boc N'Boc 3-3 3-9 3-6a N-OH

NC R2 H2N2 --- Base R9 _..- R2 N
_________________________________________ ..-R1-O _______ Base N A- Ri W 0 N, NH2OH.HCI Ns Ri W
N
Boc Boc CI ).R9 'Boc 3-3 3-10 3-11 3-6b I1c) EDCI Rlo N 2 P205 N,N, R2 __________________ .- r sl\J ¨3.-R1- \OV R1 W
N, Ri v v Ns Boc Ns P2Ss Boc 3-12 3-13 Boc 3-6c 11c) NS R
)2 _Ki The cyano intermediate 3-3 and the ester intermediate 3-5 are prepared from substituted 3-2 by cynidation and 3-4 by alkylation as described in Scheme 1.
The cyano group of 3-3 and the ester group of 3-5 are converted to heterocyclic rings such as imidazole, thiazole, thiadiazole, oxadiazole 3-6 (3-6a, 3-6b, 3-6c and 3-6d), etc.
through the corresponding intermediates such as amide, thioamide, hydrazide, thiohydrazide or N-hydroxy-imidamide using the common methods exemplified in the scheme 3. The conversion of 3-6 to 3-8 is achieved using the methodology illustrated in Scheme 1.
Scheme 4 Compounds where "A" of Formula I is a heteroalkyl moiety are synthesized as illustrated in Scheme 4 and exemplified by the synthesis of 4-6.
R4 N.. R3 Me000 R2 HOOC R2 W

R1-('')R1-('')BaSe ______________ RI-('A') EDCl/HOBtR1 W
Boc Boc Boc R4 N.. R3 R4 N.. R3 R4 Nõ R3 LAH
_bR2 _,..
W -10- Ri W
Ri Ri W NH N R5 Boc R6 R7 A suitable substituted cyclic amide 4-3 is prepared from the corresponding ester 4-1 by hydrolysis using bases, such as NaOH, Li0H,KOH, or the like, followed by coupling with an amine in the presence of coupling reagents, such as EDCl/HOBt, DCC,HATU, or the like. Reduction of 4-3 using BH3 or LiA1H4, followed by deprotection of Boc group of 4-4 and alkylation of 4-5 as described in Scheme yields compound 4-6.
Scheme 5 As illustrated in Scheme 5, compounds where Y and Q of Formula I are certain moieties are synthesized.

_ ILN R2 CHO R2 ====,, R3 +-DIBAL-H
R3PPh3X
R1 W ¨).- R1 WR1 W H2 N
'Boo N,Boc N
Boc
5-2 R2 R3 R2 ,,, R3 R2 ,,, R3 R1-() 1-1 -,..' R1 W Alkylation A-- R1-() N, NH N
Boc XC\

Base NaBH4 R3-Br ¨,-- R3-CHO ¨I- R3-CH2OH ¨1--R3-CH2X 1:111 -1 R3p+ph3x-DMF
5-9 5-10 5-11 5-12 5-la Reduction of CN group to aldehyde 5-1, followed by Wittig reaction with a quaternary phosphonium salt such as 5-la produces compound 5-2. Hydrogenation of the double bond of 5-2 followed by deprotection or deprotection of 5-2 followed by the alkylation gives either an unsaturated or a saturated compound 5-8. The quaternary phosphonium salt 5-la is prepared from a suitable bromide 5-9.
Conversion of a suitable bromide 5-9 to the corresponding aldehyde 5-10, followed by reduction of the aldehyde with a suitable reducing agent, such as NaB H4 or the like, gives alcohol 5-11. Halogenation of alcohol 5-11, followed by the treatment with PPh3 gives a quaternary phosphonium salt 5-1a.
Scheme 6 As illustrated in Scheme 6, compounds where Y and Q of Formula I are other moieties than in Scheme 5 are synthesized.

R3 R2 R3 R2 R2 H+ R3 R3 [0] Alkylation R1 W R1 W ¨B-- R1 W R1 W
N, N, NH N R6 Boc Boc ipp, . .5 R7 Alcohol 2-2 is oxidized with oxidants such as Dess-Martin Periodiane, PCC, or the like to form ketone 6-1. Deprotection of the Boc group of 6-1, followed by alkylation generates 6-3.
Scheme 7 As illustrated in Scheme 7, compounds where Z and T of Formula I are particular moieties are synthesized.
RtR3 N aryl¨R4 ¨I" R1 Xs\ N aryl ¨R6 R5 R7 ppApi . .5 . .7 R4 = Br, CN, NO2, COOH, COOEt, pinacol boric ester, alkynyl R6 = alkynyl, aryl, heteroaryl The starting 7-1 is a group of intermediates which are prepared according to the schemes 1 to 6. The aryl group of 7-1 is a substituted or an unsubstituted aryl group, such as benzene, thiazolyl, thiophenyl, furanyl, imidazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl. The R4 is a functional group such as Br, I, CN, COOH, COOEt, boric acid.
The conversion of R4 to R6 is achieved via Suzuki coupling of boric acid with Br or I, or the cyclization of hydrazide of ester with acid or the cyclization of N-hydroxy-imidamide with an acyl chloride.
Scheme 8 Scheme 8 illustrates one of the approaches for the synthesis of stereo isomers. In addition, the synthesis of the two enantiomerically pure isomers is also achieved by the chiral separation via chiral HPLC, chiral resolution, or column chromatography methods.
EtO0C Et0060 HOO_r LHMDS NaOH
Ri-N) 101 ¨..- 1.1 Ri W
N. N. N
Boc Boc 'Boc )L, 1. CICO2Et Aux O 101 Aux_CO 0 ________ . +
2. Aux-Li Ri W Ri W
N N.
sBoc Boc Aux = 0-A
L......;:il: or _Xczµi3O
Aux O 0 HOt=-TO Si Ri W
N
t---) N ¨.-- Ri W 01 µBoc µBoc µBoc R1')7.0 40 Ri W -"' Ri W -'' R6 i W
N 'Boc 'Boc N. N R6 µBoc Boc Boc Boc Ac=

X = 'OH' XjL0- R2 L = leaving group: Cl, Br, I, Tos, Ms, , In scheme 8, ester 8-2, prepared according to scheme 1, is hydrolyzed to acid using inorganic bases, such as Li0H, NaOH, KOH, or the like. Acid 8-3 is activated to its corresponding acid chloride or mixed anhydride, followed by reaction with lithiated chiral auxiliary salt provides a mixture of diastereomers 8-4 and 8-5. The separation of diastereomeric mixture provides the single enantiomers 8-4 and 8-5.

The enantiomerically pure intermediates such as 8-4 and 8-5 are further transformed into a variety of the key intermediates, such as 8-8 and 8-10, in enantiomerically pure form, using the methodologies illustrated in the schemes 1-7. Some examples are illustrated in Scheme 9 and Scheme 10 below.
Scheme 9 Scheme 9 shows an example for the synthesis of enantiomerically pure compounds 9-8 starting from 8-4.

Aux O 0 HOO
t--) R2, OZ-10 I.
NaBH4 0 NaH
Ri Ns Ns R2X Ns Boc Boc Boc R2'0 's\
'OH , [H] [0] 0 R3P+Ph3X R20µ,..
R3[H]
' R+/ ¨"- R+/ ¨1"- R1 W
Ns Ns bases N.
Boc Boc Boc R2,0 0\--õ .,.. R3 R so R3 Z_.....õ) H 2,o+
R1 W ¨I" R¨) ¨,-- R1 W
Ns NH N R4 Boc Ac=

The enantiomerically pure intermediate 8-4 described in Scheme 8 is reduced using NaBH4 to a chiral alcohol 9-1. The transformation of alcohol 9-1 to 9-8 is carried out according to the methodologies described in schemes 1 to 5. Using the same methodology as demonstrated in Scheme 9, the enantiomer of 9-8 is synthesized starting from the enantiomerically pure intermediate 8-5.
Scheme 10 Scheme 10 shows an example for the synthesis of enantiomerically pure compounds 10-8 starting from 8-5.

1,, 1 AUX) " 0 0 [FA Aux) OH OH
NaH Aux)1, ''' 0R2 -NaBH4 R1 W N, Boc ¨'-' R1 W N 'Boc ¨j-R2X Ri W Ns Boc ¨I' R2 (:) OH R2.0 ,soo R2-,0 so-k,,,,,,,. R3 [FA
[0] R3P+Ph3X-R1 W ¨1' Ri W R1 WN
Boc Ns N, sBoc Boc .0 .0% `--..k...õ.., R2..0 .0õ.õ, R3 R2N0 .s.% R3 R2 R3 R1-) N
.., v,..,.. H+
¨1- R14'') NH
, Alkylation w- R1 W

Boc R5' A i;µ
. ,5 -6 The enantiomerically pure compound 10-8 is synthesized starting from 8-5 according to the methodologies described in scheme 9. Using the same methodology as demonstrated in Scheme 10, the enantiomer of 10-8 is synthesized starting from the enantiomerically pure intermediate 8-4.
Scheme 11 Scheme 11 shows an example for the synthesis of enantiomerically intermediate and 9-1 starting from 8-3 by chiral resolution.

HOO_r HOOC,,. 0 Ri W lei Resolution 0 +
Boc Boc Boc Me00C,, HOrR1, Me00C, 0 OH
W 101 ..-Ri W 101 " Ri W
N, N Ns Boc Boc Boc R2,0 OOMe R2'0 'µµµOH
_,...
R1 W Ri W
N, N
Boc 'Boc HOOC ) , =

Me00C % Z 101 'õ 0 10/ 0 0 HO?
N, N N, Boc Boc Boc The enantiomerically intermediate 10-3 and 9-1 was synthesized starting from 8-according to the methodologies described in scheme 9 and 10. Using the same methodology as demonstrated in Scheme 11, the enantiomer of 10-3 and 9-1 is synthesized starting from the enantiomerically pure intermediate 11-2.
Formulation of the Compounds (Compositions) For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stifling. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted to provide a pharmaceutically acceptable dosage of the active component.
The compounds of the invention and for some of them, their properties, are listed below in Tables Ito VI.
Table I: Compounds with a pyrrolidine ring and a pyridine or pyridine-like molecule bonded to the pyrrolidine N-constituent Co MS
mpo Structure Name (ESI+): H-NMR
und [M+H]+
No.
1HNMR (300 MHz, CDC13):
6 7.52 (d, J= 7.5 Hz, 1H), 6.95 (d, J = 7.8 Hz, 1H), 6.53-6.51 (m, 2H), 4.25-4.15 5-((R or (m, 1H), 3.45 (q, J= 5.1 Hz, S)-3-(ethoxymethyl) 2H), 3.31-3.23 (m, 2H), 0 / -3-(2-(5-methylthiop 3.15-3.03 (m, 1H), 2.95-2.81 1 hen-2-yl)ethyl)pyrro 385 l h 2 1 l d lidi (m, 1H), 2.79-2.60 (m, 3H), r) n--y)--mety-N 2.60-2.55 (m, 1H), 2.52 (s, 6,7-dihydro-5H-cycl 3H), 2.42 (s, 3H), 2.39-2.35 openta[b]pyridine (m, 1H), 2.18-2.10 (m, 2H), 2.10-1.98 (m, 1H), 1.90-1.75 (m, 2H), 1.65-1.59 (m, 2H), 1.17 (t, J= 7.2 Hz, 3H).

1HNMR (300 MHz, Me0D):
6 8.70 (s, 1H), 8.38-8.36 (m, 1H), 8.00-7.97 (m, 1H),
7.41-7.37 (m, 1H), 7.01 (d, J
(S or =5.1 Hz, 1H), 6.73 (d, J= 5.1 R)-3-(2-(3-(ethoxym Hz, 1H), 3.48 (q, J= 6.9 Hz, I \
ethyl)-3-(2-(3-methy 2H), 3.33-3.30 (m, 2H), lthiophen-2-yl)ethyl) 3.29-3.27 (m, 2H), 2.68-2.55 pyrrolidin-l-yl)prop (m, 4H), 2.53 (d, J= 9.3 Hz, an-2-yl)pyridine 1H), 2.32 (d, J=9.3 Hz, 1H), 2.11 (s, 3H), 1.78-1.64 (m, 2H), 1.62-1.55 (m, 2H), 1.44 (s, 6H), 1.17 (t, J= 6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.70 (s, 1H), 8.37 (d, J = 3.9 Hz, 1H), 7.98 (d, J= 8.1 Hz, 1H), 7.38 (m, 1H), 7.13 (dd, J
= 5.1, 1.2 Hz, 1H), 6.87 (dd, J
(S or R)-3-(2-(3-(ethoxym = 5.1, 3.3 Hz, 1H), 6.76 (d, J
= 2.4 Hz, 1H), 3.47 (q, J= 6.9 ethyl)-3-(2-(thiophe 3 359 Hz, 2H), 3.34-3.30 (m, 2H), n-2-yl)ethyl)pyrrolid in-1-yl)propan-2-y1) 2.78 (t, J= 8.4 Hz, 2H), 2.64-2.60 (m, 2H), 2.52 (d, J
pyridine =9.3 Hz, 1H),2.31 (d, J= 9.3 Hz, 1H), 1.82-1.77 (m, 2H), 1.59 (t, J= 6.9 Hz, 2H), 1.43 (s, 6H), 1.16 (t, J= 6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.77 (s, 1H), 8.13 (dd, J =
8.4, 2.4 Hz, 1H), 7.46 (d, J=
(S or 8.4 Hz, 1H), 7.17-7.16 (m, s R)-5-(2-(3-(2-ethoxy 1H), 6.90-6.87 (m, 1H), propan-2-y1)-3-(2-(t 6.80-6.79 (m, 1H), 3.50-3.29 4 hiophen-2-yl)ethyl)p 402 (m, 7H), 3.12-3.08 (m, 1H), yrrolidin-l-yl)propa 2.80 (q, J= 15.6 Hz, 4H), citrate N n-2-y1)-2-methylpyri 2.56 (s, 3H), 2.37-2.25 (m, dine citrate 1H), 1.92 (s, 6H), 1.87-1.78 (m, 3H), 1.13 (d, J= 8.7 Hz, 6H), 1.02 (t, J= 6.9 Hz, 3H) NMR (300 MHz, Me0D):
6 8.75-8.67 (m, 1H), 8.15-8.03 (m, 1H), 7.45 (t, J
5-(24(S&R)-34(S
= 6.6 Hz, 1H), 7.18-7.17 (m, Nc)(3 or R)-1-ethoxyethyl)-3-1H), 6.90-6.88 (m, 1H), 6.81 N (s, 1H), 3.56-3.50 (m, 2H), (2-(thiophen-2-yl)et 388 3.40-3.31 (m, 2H), 3.25-3.15 hyl)pyrrolidin-l-yl)p (m, 3H), 2.87-2.75 (m, 6H), citrate ropan-2-y1)-2-methy 2.58 (s, 3H), 2.33-2.08 (m, 1pyridine citrate 2H), 1.90 (d, J= 7.8 Hz, 6H), 1.87-1.62 (m, 2H), 1.36-1.00 (m, 6H) NMR (300 MHz, Me0D):
6 8.73-8.71 (m, 1H), 8.07 (t, J= 8.4 Hz, 1H), 7.45 (dd, J=
2-methyl-5-(2-((3R 8.4, 2.4 Hz, 1H), 7.27-7.12 or (m, 5H), 3.92-3.80 (m, 2H), S)-3-phenethy1-3-(te 3.65-3.26 (m, 2H), 3.47-3.38 6 trahydrofuran-2-yl)p 379 (m, 2H), 3.31 (q, J= 1.5 Hz, yrrolidin-l-yl)propa 1H), 2.80 (q, J= 15.3 Hz, citrate n-2-yl)pyridine 4H), 2.61-2.50 (m, 5H), 2.20 citrate (m, 1H), 2.15-1.95 (m, 3H), 1.87 (s, 3H), 1.85 (s, 3H), 1.77-1.72 (m, 3H), 1.28-1.15 (m, 1H) NMR (300 MHz, Me0D):
6 8.89 (s, 1H), 8.00 (d, J=
5-(2-((3R or 4.8 Hz, 1H), 7.62 (d, J= 8.1 S)-3-(tetrahydrofura Hz, 1H), 7.12-7.11 (m, 1H), I s\ n-2-y1)-3-(2-(thioph 6.92-6.91 (m, 1H), 6.80 (s, 7 en-2-yl)ethyl)pyrroli 439 -r-\-\HQ/J ¨cF3 din-1-yl)propan-2-y1 1H), 3.86-3.82 (m, 2H), 3.74-3.71 (m, 1H), 2.90-2.85 )-2-(trifluoromethyl) (m, 2H), 2.70-2.51 (m, 3H), pyridine 2.47-2.36 (m, 2H), 1.96-1.42 (m, 13H) 1H NMR (300 MHz,CDC13):
2-methyl-5-(2-((R or 58.60(d, J= 1.5 Hz, 1H), S)-3-((S or 7.72 (dd, J= 6.0, 1.5 Hz, R)-tetrahydrofuran-2 1H), 7.11-7.08 (m, 2H), 6.91 8 s-- -y1)-3-(2-(thiophen- 387 (dd, J= 2.4, 3.9 Hz, 1H), 2-yl)ethyl)pyrrolidin 6.79 (d, J= 1.8 Hz, 1H), -1-yl)propan-2-yl)py 3.87-3.83 (m, 2H), 3.73-3.71 ridine (m, 1H), 3.00-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.59-2.53 (m, 3H), 2.51 (s, 3H), 2.43 (d, J= 6.9 Hz, 1H), 2.00-1.91 (m, 1H), 1.90-1.85 (m, 3H), 1.78-1.71 (m, 3H), 1.61-1.52 (m, 1H), 1.39 (d, J = 0.9 Hz, 6H) 1H NMR (300 MHz, CDC13):
6 8.57 (s, 1H), 7.63 (d, J=
2-methyl-5-(2-((3S 7.5 Hz, 1H), 7.12 (s, 1H), or 7.07 (d, J= 8.1 Hz, 1H), 6.93 r R)-3-(tetrahydrofura (s, 1H), 6.81 (s, 1H),
9 s n-2-y1)-3-(thiophen- 371 3.88-3.78 (m, 1H), 3.76-3.69 2-ylmethyl)pyrrolidi (m, 3H), 3.15-3.10 (m, 1H), ¨
n-1-yl)propan-2-yl)p 2.95-2.83 (m, 1H), 2.52 (s, yridine 3H), 2.48-2.36 (m, 3H), 1.76-1.60 (m, 6H), 1.36 (s, 3H), 1.35 (s, 3H) 1H NMR (300 MHz, Me0D):
6 8.68 (d, J=2.1 Hz, 1H), 8.02 (dd, J= 8.3, 2.1 Hz, 1H), 7.43-7.34 (m, 5H), 7.32-7.26 (m, 1H), 7.14 (d, J
5-(2-((R or S)-3-((S
=5.1 Hz, 1H), 6.88-6.85 (m, or ¨\o R)-ethoxy(phenyl)m 1H), 6.74 (d, J=2.4 Hz, 1H), 4.39 (s, 1H), 3.41-3.35 (m, / I ethyl)-3-(2-(thiophe 449 2H), 3.28-3.25 (m, 2H), n-2-yl)ethyl)pyrrolid = 3.16-3.06 (m, 2H), 2.92-2.83 in-1-yl)propan-2-y1) (m, 2H), 2.84-2.71 (m, 4H), -2-methylpyridine 2.56 (s, 3H), 2.25-2.13 (m, 1H), 2.90-2.81 (m, 1H), 1.77-1.73 (m, 6H), 1.61-1.50 (m, 2H), 1.05 (t, J=6.9 Hz, 3H) 1H NMR (300 MHz, CDC13):
6 8.53 (d, J=2.4 Hz, 1H), 5-(2-((R or S)-3-((R 7.60 (dd, J= 8.1, 2.4, Hz or 1H), 7.32-7.28 (m, 5H), o S)-ethoxy(phenyl)m 7,10-7.04 (m, 2H), 6.90 (dd, 11 / ethyl)-3-(2-(thiophe 449 J=5.1, 3.6 Hz, 1H), 6.76 (d, n-2-yl)ethyl)pyrrolid J= 2.4 Hz, 1H), 4.20 (s, 1H), in-1-yl)propan-2-y1) 3.41-3.30 (m, 1H), 3.27-3.12 -2-methylpyridine (m, 1H), 3.05-2.92 (m, 1H), 2.91-2.82 (m, 1H), 2.74 (d, J
= 9.2 Hz, 1H), 2.52 (s, 3H), 2.51-2.45 (m, 1H), 2.41-2.30 (m, 1H), 2.24 (d, J= 9.0 Hz, 1H), 2.02-1.88 (m, 2H), 1.71-1.65 (m, 2H), 1.37 (s, 3H), 1.34 (s, 3H), 1.15 (t, J=
6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.70 (d, J= 2.1 Hz, 1H), 8.05 (dd, J= 8.1, 2.4, Hz 1H), 7.41 (d, J= 8.1 Hz, 1H), 5-(2-((R or S)-3-((R 7.16 (dd, J=5.1, 1.2 Hz, 0 or 1H), 6.88 (dd, J= 5.1, 3.3 \ S)-1-ethoxyethyl)-3- Hz, 1H), 6.79 (d, J= 3.3 Hz, 12 S (2-(thiophen-2-yl)et 387 1H), 3.61-3.58 (m, 1H), hyl)pyrrolidin-l-yl)p 3.50-3.34 (m, 1H), 3.32-3.30 ropan-2-y1)-2-methy (m, 2H), 3.25-3.22 (m, 2H), citrate 1pyridine citrate 3.21-3.19 (m, 1H), 2.92-2.82 (m, 2H), 2.80-2.70 (m, 4H), 2.56 (s, 3H), 2.09-1.95 (m, 1H), 1.94-1.85 (m, 3H), 1.82 (s, 6H), 1.10-1.03 (m, 6H) 1HNMR (300 MHz, Me0D):
6 8.69 (d, J= 2.1 Hz, 1H), 8.03 (d, J= 8.7 Hz, 1H), 7.42 (d, J= 7.2 Hz, 1H), 7.17 (dd, 5-(2-((R or S)-3-((S J= 4.8, 1.2, Hz, 1H), 6.88 0 or (dd, J= 3.3, 5.1 Hz 1H), 6.79 \ R)-1-ethoxyethyl)-3- (d, J= 3.0 Hz, 1H), 3.68-3.60 13 s-- (2-(thiophen-2-yl)et 387 (m, 1H), 3.49-3.43 (m, 1H), hyl)pyrrolidin-l-yl)p 3.30-3.18 (m, 4H), 3.17-2.98 N ropan-2-y1)-2-methy (m, 2H), 2.86-2.71 (m, 4H), citrate 1pyridine citrate 2.56 (s, 3H), 2.25-2.12 (m, 1H), 2.10-1.90 (m, 1H), 1.82 (s, 6H), 1.81-1.76 (m, 2H), 1.71-1.60 (m, 1H), 1.13-1.03 (m, 6H) 1HNMR (300 MHz, Me0D):
\--\0 (R or S)-2-methyl-5-(2-(3- 6 8.68 (d, J=2.1 Hz, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.41 \ CT (propoxymethyl)-34 (d, J=8.4 Hz. 1H), 7.15 (d, J
14 N s 2-(thiophen-2-yl)eth 387 =5.1 Hz, 1H), 6.88 (dd, J=
yl)pyrrolidin-l-yl)pr 5.1, 3.6 Hz, 1H), 6.78 (d, J
opan-2-yl)pyridineci citrate =3.3 Hz, 1H), 3.50-3.38 (m, trate 2H), 3.25-3.20 (m, 2H), 3.12-3.08 (m, 1H), 2.92-2.87 (m, 2H), 2.78-2.72 (m, 4H), 2.56 (s, 3H), 2.15-1.92 (m, 2H), 1.90-1.81 (m, 4H), 1.79 (s, 6H), 1.70-1.48 (m, 3H), 0.89 (t, J=7.5 Hz, 3H) 1H NMR (300 MHz, Me0D):6 8.56 (d, J= 2.4 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), (R or 7.27 (d, J= 8.2 Hz, 1H),7.13 S)-1-((3-(ethoxymet hyl)-1-(2-(6-methylp (d, J=6.8 Hz, 1H), 7.10-6.96 yridin-3-yl)propan-2 (m, 3H), 3.92-3.81 (m, 3H), oNI
o¨\ VI
3.40-3.30 (m, 4H), 3.31 (m, 15 ) -yl)pyrrolidin-3-y1) 437 2H), 3.18 (s, 2H), 2.91 (d, J
N citrate methyl)-3-ethyl-1,3-dihydro-2H-benzo[d = 11.5 Hz, 1H), 2.78-2.61 (m, 4H), 2.45 (s, 3H), 1.96 limidazol-2-one (m, 1H), 1.83-1.72 (m, 1H), citrate 1.65 (s, 3H), 1.64 (s, 3H),1.20 (t, J= 7.2 Hz, 3H), 1.06 (t, J= 6.9 Hz, 3H) 1H NMR (300 MHz, CDC13):
6 8.51 (d, J= 2.1 Hz, 1H), 7.64 (dd, J= 8.1, 2.4 Hz, (R or 1H), 7.07-7.02 (m, 2H), 6.86 S)-5-(2-(3-(2-ethoxy (dd, J= 5.1, 3.3 Hz, 1H), C S - 1, 1,1,3,3,3-hexafluo 6.74-6.73 (m, 1H), 3.96-3.80 ropropan-2-y1)-3-(2-16 509 (m, 2H), 3.01 (t, J= 8.7 Hz, (thiophen-2-yl)ethyl 2H), 2.89 (d, J= 9.6 Hz, 1H), )pyrrolidin-l-yl)pro 2.60-2.56 (m, 2H), 2.55 (s, pan-2-y1)-2-methylp 3H), 2.36-2.28 (m, 2H), yridine 2.15-2.08 (m, 1H), 2.00-1.80 (m, 2H), 1.61 (s, 6H), 1.13 (t, J= 6.9 Hz, 3H) 1H NMR (300 MHz, Me0D):
6 8.50 (d, J= 2.1 Hz, 1H), 5-(2-((R or 7.92-7.87 (m, 1H), 7.35 (dd, S)-3-(2-ethoxy-1,1,1 S J= 8.4, 2.7 Hz, 1H), \ ,3,3,3-hexafluoropro 7.19-7.16 (m, 1H), 6.93-6.90 pan-2-y1)-3-(2-(thio 17 523 (m, 1H), 6.85-6.75 (m, 1H), phen-2-yl)ethyl)pyrr olidin-l-yl)butan-2- 4.08-3.90 (m, 2H), 3.19-3.10 (m, 1H), 3.05-2.98 (m, 2H), y1)-2-methylpyridine 2.91-2.75 (m, 4H), 2.54 (s, citrate 3H), 2.50-2.35 (m, 2H), 2.22-2.10 (m, 1H), 2.09-1.90 (m, 2H), 1.89-1.75 (m, 2H), 1.46 (s, 3H), 1.35-1.30 (m, 2H), 1.22-1.16 (m, 3H), 0.71-0.64 (m, 3H) 1H NMR (300 MHz, Me0D) (R or 6 8.61 (s, 1H), 7.97 (d, J=
S)-1-((3-(ethoxymet 8.2 Hz, 1H), 7.31 (d, J=8.1 * hyl)-1-(2-(6-methylp Hz, 1H), 7.10-7.03 (m, 1H), 18 yridin-3-yl)propan-2 409 6.99-6.90 (m, 3H), 3.85 (s, citrate -yl)pyrrolidin-3-y1) 2H), 3.48-3.06 (m, 10H), methyl)-1,3-dihydro 2.84- 2.63 (q,J = 15.6 -2H-benzo [dlimidaz Hz,4H), 2.46 (s, 3H), 1.94 ol-2-one citrate (m, 2H), 1.76 (s, 6H), 1.04 (t, J= 6.9 Hz, 3H) 1H NMR (300 MHz, CDC13):
6 8.58 (d, J= 2.1 Hz, 1H), 7.69 (dd, J= 8.1, 2.4 Hz, 2-methyl-5-(2-((3R
1H), 7.12-7.05 (m, 2H), or S)-3-(tetrahydrofura 6.93-6.90 (m, 1H), 6.78 (d, J
= 3.3 Hz, 1H), 3.90-3.75 (m, 19 n-2-y1)-3-(3-(thioph 399 en-2-yl)propyl)pyrro 2H), 3.74-3.62 (m, 1H), /
¨N lidin-1-yl)propan-2-2.89-2.75 (m, 2H), 2.64-2.45 (m, 6H), 2.35-2.25 (m, 1H), yl)pyridine 1.90-1.80 (m, 4H), 1.72-1.58 (m, 4H), 1.52-1.44 (m, 2H), 1.43-1.36 (m, 6H) 1H NMR (300 MHz, CDC13):
6 8.58 (d, J=2.4 Hz, 1H), 7.68 (dd, J= 8.4, 2.4 Hz, 1H), 7.11-7.05 (m, 2H), 6.90 (dd, J= 8.4, 3.3 Hz, 1H), (R or 6.78-6.77 (m, 1H), 3.49 (s, 0 S)-5-(2-(3-(ethoxym Q ethyl)-3-(3-(thiophe 2H), 3.44 (dd, J= 14.1, 7.5 N
20 387 Hz, 2H), 3.24 (dd, J= 15.2, n-2-yl)propyl)pyrrol 8.7 Hz, 2H), 2.80 (t, J= 7.2 ¨N idin-l-yl)propan-2-y Hz, 2H), 2.60-2.55 (m, 1H), 1)-2-methylpyridine 2.54-2.50 (m, 4H), 2.43 (d, J
= 9.0 Hz, 1H), 2.23 (d, J=
9.0 Hz, 1H), 1.55-1.48 (m, 4H), 1.36 (s, 6H), 1.15 (t, J=
6.9 Hz, 3H) 1HNMR (300 MHz, CDC13):
6 8.59 (d, J= 2.1 Hz, 1H), 7.71 (dd, J=8.1,2.4 Hz, 1H), 7.10-7.06 (m, 2H), 6.91 (R or S)-5-(2-(3-(isopropo (dd, J= 5.1, 3.3 Hz, 1H), 6.77 (d, J= 2.4 Hz, 1H), xymethyl)-3-(2-(thio h 2 1) th 1) 387 3.52-3.48 (m, 1H), 3.26 (q, J

P en- -Y e Y PYrr = 8.7 Hz, 2H), 2.79 (t, J= 8.4 olidin-1-yl)propan-.2 Hz, 2H), 2.58-2.52 (m, 5H), -y1)-2-methylpyrichn 2.28 (d, J= 9.0 Hz, 1H), 2.95-2.75 (m, 2H), 2.55-2.50 (m, 2H), 1.37 (s, 6H), 1.30-1.26 (m, 1H), 1.14-1.12 (m, 6H) 1HNMR (300 MHz, CDC13):
6 8.52 (s, 1H), 7.64 (dd, J=
8.1, 2.4 Hz, 1H), 7.10-7.07 (m, 2H), 6.91 (d, J= 2.1 Hz, 5-(2-((R or 1H), 6.77 (d, J= 0.9 Hz, 1H), o S)-3-(isopropoxymet 3.55-3.45 (m, 1H), 3.35-3.20 \__Cr hyl)-3-(2-(thiophen-401 (m, 2H), 2.85-2.72 (m, 2H), s-- 2-yl)ethyl)pyrrolidin 2.70-2.60 (m, 1H), 2.53 (s, -1-yl)butan-2-y1)-2- 3H), 2.50-2.40 (m, 2H), 2.35-N methylpyridine 2.18 (m, 1H), 1.90-1.73 (m, 3H), 1.68-1.62 (m, 1H), 1.57-1.52 (m, 2H), 1.34 (s, 3H), 1.15-1.11 (m, 6H), 0.62 (t, J=7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
68.68 (s, 1H), 8.04 (d, J=8.1 (R or Hz, 1H), 7.40 (d, J= 7.9 Hz, S)-1-((3-(ethoxymet hyl)-1-(2-(6-methylp 1H), 7.20-7.16 (m, 1H), AL yridin-3-yl)propan-2 7.06-7.02 (m, 1H), 6.85 (t, 9.6 F
Hz, 1H), 3.94-3.90 (m, 4H), 4.1\1- citrate -yl)pyrrolidin-3-y1) 455 3.50-3.27 (m, 7H), 3.05 (d, J
methyl)-3-ethyl-5-fl uoro-1,3-dihydro-2H = 11.4 Hz, 1H), 2.81 (q,J =
15.6 Hz, 4H), 2.56 (s, 3H), -benzo[dlimidazol-2 2.10-1.99 (m, 2H), 1.84-1.73 -onecitrate (m, 6H), 1.32-1.24 (m, 3H), 1.15 (t, J= 6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):(5 8.55 (s, 1H), 7.95 (dd,J =8.1,2.4 Hz, 1H), 7.30 (R or (d, J= 8.4 Hz, 1H), 7.07 (d, J
S)-2-methy1-5-(1-(2-= 4.8 Hz, 1H), 6.78 (t, J=4.2 sNs/N (6-methylpyridin-3-Hz, 1H), 6.67 (d, J= 2.7 Hz, yflpropan-2-y1)-3-(2 24 413 1H), 3.42 (d, J=11.2 Hz, \S".-1 -(thiophen-2-yl)ethy citrate 1)pyrrolidin-3-y1)-1, 1H), 3.05-2.96 (m, 1H), 2.94-2.83 (m, 1H), 2.70 (m, 3,4-thiadiazole 6H), 2.52 (m, 2H), 2.47 (s, citrate 3H), 2.30 (m, 1H), 2.11 (s, 3H), 2.03-1.93 (m, 1H), 1.85 (m, 1H), 1.61 (s, 6H) 1HNMR (300 MHz, Me0D):
6 8.68 (s, 1H), 8.02 (d, J=8.1 (R or Hz, 1H), 7.73 (dd, J= 9.0, 4.8 o S)-5-(2-(3-(ethoxym Hz, 1H), 7.39 (s, 1H), 7.36 (s, ethyl)-3-(2-(5-fluoro 1H), 7.07-7.00 (m, 2H), benzo[b]thiophen-2- 3.50-3.45 (m, 2H), 3.38-3.43 citra yl)ethyl)pyrrolidin-1 .. (m, 2H), 3.27-3.20 (m, 2H), -yl)propan-2-y1)-2- 3.15-3.08 (m, 1H), 2.92-2.85 methylpyridine (m, 3H), 2.79 (q, J= 15.6 Hz, citrate 4H), 2.54 (s, 3H), 1.98-1.82 (m, 4H), 1.77 (s, 6H), 1.14 (t, J= 6.9 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 8.70 (s, 1H), 8.04 (d, J=
6.0 Hz, 1H), 7.44 (d, J= 8.2 (S or Hz, 1H), 7.24 (d, J= 5.3 Hz, 0 R)-5-(2-(3-(ethoxym 1H), 6.95-6.90 (m, 1H), 6.82 / ethyl)-3-(thiophen-2 (s, 1H), 3.47-3.40 (m, 2H), 26 citrat -ylmethyl)pyrrolidin 359 3.20-3.19 (m, 3H), 3.10-3.07 -1-yl)propan-2-y1)-2 (m, 3H), 3.05-2.98 (m, 2H), -methylpyridine 2.82 (q, J= 15.6 Hz, 4H), citrate 2.59 (s, 3H), 2.06-1.96 (m, 1H), 1.93-1.86 (m, 1H), 1.83 (s, 6H), 1.15 (t, J= 7.0 Hz, 3H).

1HNMR (300 MHz, Me0D):
6 8.66 (d, J= 2.1 Hz, 1H), 8.53 (dd, J= 4.8, 1.2 Hz, 1H), 8.27 (d, J= 8.1 Hz, 1H), 8.01 (R or (dd, J= 4.8, 1.2 Hz, 1H), 7.36 ¨\o¨\ N S)-2-(2-(3-(ethoxym (d, J= 8.4 Hz, 1H), 7.30 (dd, ) (TL; ethyl)-1-(2-(6-methy J= 7.8, 3.6 Hz, 1H), 7.23 (s, N s 27 1pyridin-3-yl)propan 424 1H), 3.52-3.44 (m, 2H), ¨r citrate -2-yl)pyrrolidin-3-y1 3.38-3.35 (m, 2H), 3.18-3.10 )ethyl)thieno[3,2-blp (m, 2H), 3.08-3.02 (m, 1H), yridine citrate 2.96 (t, J= 8.4 Hz, 2H), 2.92-2.87 (m, 1H), 2.80 (q, J
= 15.6 Hz, 4H), 2.53 (s, 3H), 2.00-1.83 (m, 4H), 1.74 (s, 6H), 1.14 (t, J= 6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.68 (d, J= 1.8 Hz, 1H), 8.40(d, J= 3.3 Hz, 1H), (R or 8.10-8.02 (m, 2H), 7.39-7.34 ¨\o S)-2-(2-(3-(ethoxym (m, 2H), 7.08 (s, 1H), ethyl)-1-(2-(6-methy 3.50-3.42 (m, 2H), 3.38-3.36 I
28 N S N 1pyridin-3-yl)propan 424 (m, 1H), 3.25-3.18 (m, 2H), ... citrate -2-yl)pyrrolidin-3-y1 3.15-3.10 (m, 1H), 3.09-3.00 )ethyl)thieno[2,3-blp (m, 1H), 2.99-2.88 (m, 3H), yridine citrate 2.81 (q, J= 15.6 Hz, 4H), 2.54 (s, 3H), 2.02-1.88 (m, 4H), 1.77 (s, 6H), 1.14 (t, J=
7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.67 (d, J= 1.9 Hz, 1H), 8.03 (dd, J= 8.2, 2.4 Hz, 1H), 7.39 (d, J= 8.3 Hz, 1H), (S&
7.18-7.14 (m, 4H), 4.01-3.87 R)-1-(2-(3-(ethoxym 5--N^ ethyl)-1-(2-(6-methy (m, 4H), 3.49-3.41 (m, 2H), o¨\

yr_N* 1pyridin-3-yl)propan 451 3.38-3.34 (m, 2H), 3.23-3.18 'N' -2-yl)pyrrolidin-3-y1 (m, 2H), 3.10 (d, J= 11.5 Th0 )ethyl)-3-ethyl-1,3-d Hz, 1H), 2.94 (d, J= 11.7 ihydro-2H-benzo[d]i Hz, 1H), 2.80 (q, J= 15.5 midazol-2-one Hz, 4H), 2.55 (s, 3H), 2.01-1.82 (m, 4H), 1.77 (s, 6H), 1.29 (t, J= 7.2 Hz, 3H), 1.13 (t, J= 7.0 Hz, 3H).

1H NMR (300 MHz, Me0D):
6 8.70 (d, J=2.5 Hz, 1H), 8.06 (dd, J= 8.3, 2.6 Hz, (R or 1H), 7.42 (d, J= 8.3 Hz, 1H), S)-5-(2-(3-(ethoxym 7.33 (d, J= 3.8 Hz, 1H), 6.87 / s\ c3 ethyl)-3-(2-(5-(triflu (d, J= 3.5 Hz, 1H), 3.52-3.43 oromethyl)thiophen-30 citrate 425 (m, 2H), 3.37-3.33 (m, 1H), 2-yl)ethyl)pyrrolidin -1-yl)propan-2-y1)-2 3.28-3.22 (m, 2H), 3.17 (d, J
-methylpyridine = 11.7 Hz, 1H), 2.98 (d, J=
citrate 11.7 Hz, 1H), 2.80 (m, 7H), 2.56 (s, 3H), 2.05-1.84 (m, 4H), 1.81 (s, 6H), 1.13 (t, J=
7.0 Hz, 3H).
1H NMR (300 MHz, Me0D):
6 8.68 (d, J=2.4 Hz, 1H), 8.04 (dd, J= 8.3, 2.5 Hz, (R or 1H), 7.41 (d, J=8.3 Hz, 1H), S)-5-(2-(3-(2-(4-chl 6.48 (d, J= 3.4 Hz, 1H), F oro-5-fluorothiophe 3.49-3.41 (m, 2H), 3.40-3.37 s n-2-yflethyl)-3-(etho 31 425 (m, 2H), 3.35-3.32 (m, 2H), citrate xymethyl)pyrrolidin -1-yl)propan-2-y1)-2 3.30-3.22 (m, 2H), 3.09 (d, J
-methylpyridine = 11.5 Hz, 1H), 2.80 (q, J=
citrate 15.5 Hz, 4H), 2.69-2.59 (m, 2H), 2.56 (s, 3H), 2.09-1.82 (m, 3H), 1.78 (s, 6H), 1.13 (t, J= 7.0 Hz, 3H).
1H NMR (500 MHz, Me0D):
6 8.54 (d, J= 2.1 Hz, 1H), 7.87 (dd, J= 8.2, 2.3 Hz, 1H), (R or 7.28-7.22 (m, 2H), 7.12 (d, J
S)-5-(2-(3-(2-(4-chl = 3.4 Hz, 1H), 3.47 (q, J=7.0 s orothiophen-3-yl)eth Hz, 2H), 3.34-3.32 (m, 1H), 32 y1)-3-(ethoxymethyl 407 3.30-3.29 (m, 1H), 2.69-2.62 )pyrrolidin-l-yl)pro (m, 2H), 2.56-2.52 (m, 3H), pan-2-y1)-2-methylp 2.50 (s, 3H), 2.37 (d, J= 9.2 yridine Hz, 1H), 1.74-1.66 (m, 2H), 1.63 (t, J= 6.9 Hz, 2H), 1.45 (s, 6H), 1.16 (t, J= 7.0 Hz, 3H).

1H NMR (300 MHz, CDC13):
6 8.66 (s, 1H), 7.74 (t, J= 6.3 (R or Hz, 1H), 7.21 (d, J= 8.0 Hz, CI S)-5-(2-(3-(2-(4-chl 1H), 6.89 (d, J=6.2 Hz, 1H), \ orothiophen-2-yl)eth 6.66 (m, 1H), 3.73 (t, J= 7.3 33 y1)-3-(ethoxymethyl 407 Hz, 1H), 3.68-3.21 (m, 7H), )pyrrolidin-l-yl)pro 2.87-2.69 (m, 2H), 2.60 (s, pan-2-y1)-2-methylp yridine 3H), 2.05-1.89 (m, 2H), 1.86-1.71 (m, 2H), 1.63 (s, 6H), 1.17-1.12 (m, 3H).
1H NMR (300 MHz, Me0D):
6 8.59 (dd, J=9.0,2.1 Hz, 1H), 7.69 (d, J= 8.1 Hz, 1H), 5-(2-((R & S)-3-((S
7.09 (d, J= 8.1 Hz, 1H), 6.33 cF3 or I F (t, J= 3.0 Hz, 1H), 6.23 (dd, J
0 s R)-1-ethoxy-2,2,2-tr = 2.1, 1.2 Hz, 1H), 3.95-3.82 ifluoroethyl)-3-(2-(5 34 459 (m, 1H), 3.55-3.45 (m, 2H), -fluorothiophen-2-y1 2.91-2.80 (m, 1H), 2.69-2.60 )ethyl)pyrrolidin-l-y (m, 2H), 2.53 (s, 3H), 1)propan-2-y1)-2-met 2.48-2.39 (m, 1H), 2.10-1.85 hylpyridine (m, 2H), 1.84-1.55 (m, 4H), 1.39 (s, 6H), 1.15 (t, J= 6.9 Hz, 3H) 1H NMR (300 MHz, Me0D):
68.69 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.41 (d, J= 8.1 Hz, 5-(2-((R or S)-3-((S
1H), 6.41 (m, 1H), 6.30 (d, J
or = 2.1 Hz, 1H), 3.65-3.57 (m, ¨\o R)-1-ethoxyethyl)-3-1H), 3.48-3.39 (m, 1H), I (2-(5-fluorothiophen 405 3.28-3.14 (m, 4H), 3.12-2.95 -2-yl)ethyl)pyrrolidi N.., citrate (m, 2H), 2.75 (q, J= 15.5 Hz, n-1-yl)propan-2-y1)-4H), 2.68-2.63 (m, 2H), 2.56 2-methylpyridine (s, 3H), 2.24-2.08 (m, 1H), citrate 2.06-1.94 (m, 1H), 1.69 (s, 6H), 1.68-1.59 (m, 1H), 1.12-1.02 (m, 6H) CF3 (R or 1HNMR (300 MHz, Me0D):
b_cF3 S)-5-(2-(3-(2-ethoxy 6 8.58 (d, J= 1.8 Hz, 1H), \ -1,1,1,3,3,3-hexafluo 7.68 (dd, J= 8.1, 1.8 Hz, 1H), S--NF ropropan-2-y1)-3-(2- 7.10 (d, J= 8.1 Hz, 1H), 6.36 (5-fluorothiophen-2- (d, J= 3.3 Hz, 1H), 6.25 (dd, yl)ethyl)pyrrolidin-1 J= 3.6, 1.8 Hz, 1H), -yl)propan-2-y1)-2- 3.97-3.88 (m, 2H), 2.95-2.89 methylpyridine (m, 3H), 2.71-2.56 (m, 2H), 2.53 (s, 3H), 2.45-2.30 (m, 2H), 2.18-2.02 (m, 1H), 1.92-1.80 (m, 1H), 1.72-1.65 (m, 1H), 1.40 (s, 6H), 1.20 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D):
6 8.70(d, J= 1.8 Hz, 1H), 8.06 (dd, J= 8.4, 2.4 Hz, 1H), 5-(2-((R or S)-3-((R 7.42 (d, J=8.4 Hz, 1H), 6.41 or (d, J=3.6 Hz, 1H), 6.30 (m, S)-1-ethoxyethyl)-3- 1H), 3.63-3.55 (m, 1H), (2-(5-fluorothiophen 3.50-3.44 (m, 1H), 3.38-3.32 citrate -2-yl)ethyl)pyrrolidi (m, 2H), 3.26-3.18 (m, 2H), n-1-yl)propan-2-y1)- 2.96-2.88 (m, 1H), 2.76 (q, J
2-methylpyridine = 15.5 Hz, 4H), 2.69-2.61 (m, citrate 2H), 2.56 (s, 3H), 2.05-1.97 (m, 1H), 1.95-1.89 (m, 1H), 1.83 (s, 6H), 1.80-1.74 (m, 2 H), 1.11-1.00 (m, 6H) 1H NMR (300 MHz, Me0D):
68.66 (s, 1H), 8.04 (d, J=8.2 (R or Hz, 1H), 7.40 (d, J= 8.2 Hz, HN¨e S)-(3-(2-(5-fluorothi 1H), 6.42 (m, 1H), 6.35-6.25 o ophen-2-yl)ethyl)-1- (m, 1H), 4.08-3.91 (m, 2H), I (2-(6-methylpyridin- 3.83-3.73 (m, 2H), 3.18 (m, citrate 3-yl)propan-2-yl)pyr 2H), 2.97 (d, J= 10.9 Hz, rolidin-3-yl)methyl 1H), 2.90-2.73 (m, 6H), isopropylcarbamate 2.71-2.64 (m, 2H), 2.56 (s, citrate 3H), 1.85-1.78 (m, 2H), 1.73 (s, 6H), 1.10 (d, J= 6.5 Hz, 6H).
1H NMR (300 MHz, Me0D):
(R or 6 8.66 (s, 1H), 8.05 (d, J=
S)-(3-(2-(5-fluorothi 8.2 Hz, 1H), 7.42 (d, J=7.8 HN¨eo ophen-2-yl)ethyl)-1-' II (2-(6-methylpyridin- Hz, 2H), 7.36 (d, J= 8.3 Hz, 482 1H), 7.28 (t, J= 7.9 Hz, 2H), citrate 3-yl)propan-2-yl)pyr rolidin-3-yl)methyl 7.03 (t, J= 7.3 Hz, 1H), 6.43 phenylcarbamate (m, 1H), 6.28 (m, 1H), 4.09 citrate (q, J= 11.1 Hz, 2H), 3.18 (m, 2H), 2.99 (m, 1H), 2.90-2.68 (m, 5H), 2.49 (s, 3H), 1.96-1.79 (m, 4H), 1.73 (s, 6H).
1HNMR (300 MHz, Me0D):
68.66 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.39 (d, J= 8.1 Hz, isopropyl (S or 1H), 6.42 (t, J=3.3 Hz, 1H), 04N R)-((3-(2-(5-fluoroth 6.28 (dd, J= 2.4, 1.2 Hz, 1H), H iophen-2-yl)ethyl)-1 cN \ -ON 4.88-4.68 (m, 2H), 3.25-3.13 40 s F -(2-(6-methylpyridin 448 citrate _3-yl)propan-2-yl)py (m, 4H), 3.05-2.93 (m, 1H), 2.73 (q, J= 15.6 Hz, 4H), rrolidin-3-yl)methyl) 2.71-2.62 (m, 2H), 2.55 (s, carbamate citrate 3H), 1.92-1.80 (m, 2H), 1.75 (s, 6H), 1.68-1.63 (m, 2H), 1.26 (m, 6H) 1HNMR (300 MHz, Me0D):
6 8.53 (d, J= 1.2 Hz, 1H), phenyl (S or 7.89 (dd, J= 6.0, 2.4 Hz, 1H), Ph R)-((3-(2-(5-fluoroth 7.36 (t, J= 7.8 Hz, 2H), 7.23 b¨FfNi¨x iophen-2-yl)ethyl)-1 (d, J= 8.1 Hz, 1H), 7.20 (m, 41 ) -(2-(6-methylpyridin 482 1H), 7.08 (d, J= 7.8 Hz, 2H), N S
-3-yl)propan-2-yl)py 6.42 (t, J= 3.3 Hz, 1H), 6.28 rrolidin-3-yl)methyl) (dd, J= 3.3, 2.1 Hz, 1H), carbamate 2.85-2.70 (m, 7H), 2.55 (m, 1H), 2.49 (s, 3H), 1.80-1.60 (m, 4H), 1.45 (s, 6H) IHNMR (300 MHz, Me0D):
6 8.72 (s, 1H), 8.08 (d, J=
(S or 8.3 Hz, 1H), 7.43 (d, J= 8.2 R)-1-((3-(2-(5-fluor iPHr\NION
othiophen-2-yl)ethyl Hz, 1H), 6.50-6.40 (m, 1H), / I 42 N S )-1-(2-(6-methylpyri 6.35-6.25 (m, 1H), 3.91-3.73 citrate din-3-yl)propan-2-y1 (m, 1H), 3.22-3.09 (m, 3H), )pyrrolidin-3-yl)met 2.90 (d, J= 4.8 Hz, 1H), hyl)-3-isopropylurea 2.88-2.65 (m, 8H), 2.57 (s, citrate 3H), 1.88-1.68 (m, 10H), 1.12 (m, 6H).
(S or IHNMR (300 MHz, Me0D):
Ph ,0 1-11\1-4( R)-1-((3-(2-(5-fluor HN 6 8.71 (s, 1H), 8.09 (d, J=
/ othiophen-2-yl)ethyl 43 481 8.4 Hz, 1H), 7.41-7.33 (m, N S F )-1-(2-(6-methylpyri citrate din-3-yl)propan-2-y1 3H), 7.27 (t, J= 7.8 Hz, 2H), )pyrrolidin-3-yl)met 7.00 (t, J=7.2 Hz, 1H), hyl)-3-phenylurea 6.48-6.44 (m, 1H), 6.34-6.26 citrate (m, 1H), 3.44-3.34 (m, 3H), 3.18 (m, 1H), 2.95 (m, 1H), 2.91-2.68 (m, 7H), 2.50 (s, 3H), 2.00-1.87 (m, 2H), 1.84 (m, 6H), 1.81-1.71 (m, 2H).
44 (R or 315 1H NMR (300 MHz, Me0D):
S)-(3-(4-fluorophene 6 8.69 (s, 1H), 8.63 (d, J = 4.8 thyl)-1-(pyridin-3-y1 Hz, 1H), 8.03 (s, 1H), 7.54 (s, HO methyl)pyrrolidin-3- 1H), 7.21 (dd, J = 8.4, 5.4 Hz, yl)methanol citrate 2H), 6.98 (t, J = 8.6 Hz, 2H), Ir. citrate 4.45-4.26 (m, 2H), 3.57 (s, 4H), 3.06 (d, J = 10.5 Hz, 1H), 2.87-2.71 (m, 5H), 2.59 (t, J = 8.6 Hz, 2H), 2.04 (s, 2H), 1.81 (d, J = 9.2 Hz, 2H).
45 (R or 361 1H NMR (300 MHz, Me0D):
S)-3((3-(ethoxymet 6 8.58 (s, 2H), 7.91 (d, J=9.1 hyl)-3-(4-fluorophen Hz, 1H), 7.26-7.15 (m, 2H), ethyl)pyrrolidin-1-y1 6.98 (t, J= 8.6 Hz, 2H), )methyl)-5-fluoropyr 4.54-4.35 (m, 2H), 3.61-3.51 idine citrate (m, 2H), 3.49-3.34 (m, 5H), I citrate 3.15 (d, J=11.5 Hz, 1H), 2.81 (q, J= 15.6 Hz, 4H), 2.59 (s, 2H), 2.04 (s, 2H), 1.84 (d, J= 11.9 Hz, 2H), 1.22 (t, J= 7.0 Hz, 3H).
46 (R or 0 S)-3-(ethoxymethyl) * F -3-(4-fluoropheneth HN".0 y1)-N-(pyridin-3-y1) pyrrolidine-l-carbox amide 47 ¨\0 (R or S)-3-(2-(3-(ethoxym ethyl)-3-(4-fluoroph enethyl)pyrrolidin-1 N
-yl)ethyl)pyridine 48 (R or S)-3,3'-((3-(ethoxym ethyl)-3-(4-fluoroph I I enethyl)pyrrolidin-1 N N
-yl)methylene)dipyri dine 49 (R or ¨\o S)-N-(3-(ethoxymet F
N
I hyl)-3-(4-fluorophen FIN.,yr.
ethyl)pyrrolidin- 1-y1 N )pyridin-3-amine 50 3-(1-((R or ¨\o S)-3-(ethoxymethyl) F -3-(4-fluoropheneth N
F3C-j yl)pyrrolidin- 1-y1)-2 r). N ,2,2-trifluoroethyl)p yridine 51 (R or ¨\
o S)-3,5-dichloro-4-(( F 3-(ethoxymethyl)-3-N CI
4-fluoro heneth 1 ( P Y )P
a yrrolidin-l-yl)methy 1)pyridine 52 (R or ¨\ S)-4-(2-(3-(ethoxym CN ethyl)-1-(pyridin-3-y N
CO lmethyl)pyrrolidin-3 N -yl)ethyl)benzonitril e 53 F (R or _c S)-3((3-(ethoxymet o hyl)-3-(4-fluorophen ethyl)pyrrolidin-l-y1 N I\J ---CN )methyl)isonicotinon /¨ itrile 54 F (R or S)-3((3-(ethoxymet c o hyl)-3-(4-fluorophen ethyl)pyrrolidin-l-y1 N )methyl)picolinonitri NC)- le N
55 (R or ¨\
o S)-5((3-(ethoxymet F hyl)-3-(4-fluorophen N
t),Ie ethyl)pyrrolidin-l-y1 )methyl)-2-methoxy pyridine 56 (R or ¨\
0 S)-54(3-((3 F hyl)-3-(4-fluorophen N
ethyl)pyrrolidin- 1-y1 b' NC Cr' )methyl)-2-methoxyi sonicotinonitrile 57 (R or F
S)-3((3-(ethoxymet hyl)-3-(4-fluorophen N
ethyl)pyrrolidin- 1-y1 H2N )methyl)picolinamid o e 58 5-((R or F
S)-3-(ethoxymethyl) -3-(4-fluoropheneth N
yl)pyrrolidin- 1-y1)-6 HN N--- ,7 -dihydro- 1,7 -napht o hyridin-8(5H)-one 59 5-((R or F S)-3-(ethoxymethyl) -3-(4-fluoropheneth N yl)pyrrolidin- 1-y1)-6 I ,6-dimethy1-6,7-dihy HN N-0' dro- 1,7 -naphthyridin o -8(5H)-one 60 (R or ¨\0 S)-4-(2-( 1 -(di(pyridi CN n-3-yl)methyl)-3-(et N
hoxymethyl)pyrrolid I I
in-3-yl)ethyl)benzon itrile 61 ¨\0 (R or S)-2-(3-(ethoxymeth F
N y1)-3-(4-fluorophene thyl)pyrrolidin- 1-y1) --... N - 1-(6-methylpyridin-3-yl)ethan- 1 -one 62 (R or ¨\ S)-2-(3-(ethoxymeth F y1)-3-(4-fluorophene N
0 thyl)pyrrolidin- 1-y1) -2-methyl- i-(6-meth "... N
ylpyridin-3-yl)propa n-1 -one 63 (R or ¨\o S)-2-(3-(ethoxymeth ¨
F y1)-3-(2-(5-fluoropyr Lo IN
idin-2-yl)ethyl)pyrro lidin- 1 -y1)- 1 -(6-met hylpyridin-3-yl)etha n-1 -one 64 (R or ¨\o S)-2-(3-(ethoxymeth \ / F yi)-3-(2-(541U0rOpyr N N
0 idin-2-yl)ethyl)pyrro lidin- 1 -y1)-2-methyl-"... N
1 -(6-methylpyridin-3-yl)prop an- 1-one 65 CN (R or S)-4-(2-(3-(oxetan-3 N
-y1)- 1 -(pyridin-3-y1 methyl)pyrrolidin-3-N
yl)ethyl)benzonitrile 66 F (R or S)-3-((3-(4-fluoroph N enethyl)-3-(oxetan-3 -yl)pyrrolidin- 1-y1) N methyl)pyridine 67 0 CN (R or S)-4-(2-( 1 -(2-(6-met N hylpyridin-3-yl)prop an-2-y1)-3-(oxetan-3 l\r -yl)pyrrolidin-3-yl)e thyl)benzonitrile 68 0 F (R or S)5-(3-(3-(4-fluorop N henethyl)-3-(oxetan-odi-) 3-yl)pyrrolidin- 1 -y1) Nr oxetan-3-y1)-2-meth ylpyridine 69 (R or F3c S)-5-(2-(3-(1, 1, 1,3,3 0 cF3 s ,3-hexafluoro-2-met hoxypropan-2-y1)-3-(2-(thiophen-2-yl)et hyl)pyrrolidin-l-yl)p ropan-2-y1)-2-methy 1pyridine 70 (R or F3 cF s o 3 \ S)-5 -((3-(2-ethoxy- 1 , 1, 1,3,3,3-hexafluoro prop an-2-y1)-3-(2-(t hiophen-2-yl)ethyl)p yrrolidin- 1 -yl)methy 1)-2-methylpyridine 71 (R or 0 3 \ S)-34(3-(2-ethoxy- 1 , 1, 1,3,3,3-hexafluoro prop an-2-y1)-3-(2-(t hiophen-2-yl)ethyl)p yrrolidin- 1 -yl)methy 1)pyridine 72 (R or S)-5-(2-(3-(2-ethoxy F3c 0 "
- 1, 1, 1,3,3,3-hexafluo ropropan-2-y1)-3-(4-fluorophenethyl)pyrr olidin-l-yl)propan-2 -y1)-2-methylpyridin 73 (R or F3c eF F S)-5-(2-(3-(4-fluoro phenethyl)-34 1, 1, 1, 3,3,3-hexafluoro-2-methoxyprop an-2-y' )pyrrolidin-l-yl)pro pan-2-y1)-2-methylp yridine 74 F3 F (R or HO
S)-1, 1, 1,3,3,3-hexafl uoro-2-(3-(4-fluorop henethyl)-1-(2-(6-m ethylpyridin-3-yl)pr opan-2-yl)pyrrolidin -3-yl)propan-2-ol 75 (R or F3C ',F3 F S)-5-((3-(2-ethoxy-1 o ,1,1,3,3,3-hexafluoro N
propan-2-y1)-3-(4-fl N uorophenethyl)pyrro lidin-l-yl)methyl)-2-methylpyridine 76 (R or F3c CF3 F S)-3-((3-(2-ethoxy-1 o ,1,1,3,3,3-hexafluoro N
propan-2-y1)-3-(4-fl N uorophenethyl)pyrro lidin-l-yl)methyl)py ridine 77 (R or S)-4-(2-(3-(2-ethoxy -1,1,1,3,3,3-hexafluo N ropropan-2-y1)-1-(2-(6-methylpyridin-3-N
yl)propan-2-yl)pyrro lidin-3-yl)ethyl)benz onitrile 78 (R or F3C CN S)-4-(2-(3-(1,1,1,3,3 cF3 o / ,3-hexafluoro-2-met N hoxypropan-2-y1)-1-(2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)be nzonitrile 79 (R or F3C CN S)-4-(2-(3-(1,1,1,3,3 HO ,3-hexafluoro-2-hydr N oxypropan-2-y1)-1-( Ji 2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)be nzonitrile 80 F3C CF3 CN (R or S)-4-(2-(3-(2-ethoxy N
-1,1,1,3,3,3-hexafluo N ropropan-2-y1)-1-((6 -methylpyridin-3-y1) methyl)pyrrolidin-3-yl)ethyl)benzonitrile 81 (R or F3 CF3(CN S)-4-(2-(3-(2-ethoxy - 1, 1,1,3,3,3-hexafluo ropropan-2-y1)-1-(py ridin-3-ylmethyl)pyr rolidin-3-yl)ethyl)be nzonitrile 1H NMR (300 MHz, Me0D) :
6 8.63 (s, 1H), 7.98 (dd, J=
5.7, 2.7 Hz, 1H), 7.36 (d, J=
(R or 8.4 Hz, 1H), 7.17 (dd, J= 3.9, F ¨KOF S)-5-(2-(3-((difluoro 1.2 Hz, 1H), 6.88 (dd, J= 3.6, methoxy)methyl)-3-1.2 Hz, 1H), 6.79 (d, J= 3.3 82 / I (2-(thiophen-2-yl)et 395 Hz, 1H), 6.38 (t, J= 75.3 Hz, hyl)pyrrolidin-l-yl)p 1H), 3.88-3.75 (m, 2H), citrate ropan-2-y1)-2-methy 3.05-2.98 (m, 2H), 2.93-2.78 1pyridine citarte (m, 6H), 2.75-2.65 (m, 2H), 2.54 (s, 3H), 1.89-1.80 (m, 4H), 1.65 (s, 6H) 1H NMR (300 MHz, Me0D):
68.98 (s, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.45-8.31 (m, 2H), (R or 7.96 (m, 1H), 7.79 (m, 1H), S)-3((3-(ethoxymet 7.34 (d, J= 8.2 Hz, 1H), hyl)-1-(2-(6-methylp / \
yridin-3-yl)propan-2 4.53-4.37 (m, 2H), 3.41 (t, J=
83 422 7.1 Hz, 2H), 3.21-3.09 (m, -yl)pyrrolidin-3-y1) citrate 2H), 3.02-2.96 (m, 1H), methyl)-3H-imidazo &N 2.93-2.75 (m, 4H), 2.75-2.66 [4,5-clpyridine (m, 3H), 2.55 (s, 3H), citarte 1.96-1.85 (m, 1H),1.70 (m, 1H), 1.57 (m, 6H), 1.16 (t, J=
7.0 Hz, 3H).
(R or 1H NMR (300 MHz, Me0D):
s)-1((3-(ethoxymet 6 8.59 (s, 1H), 7.97 (dd, J=
c) F hyl)-1-(2-(6-methylp 8.3, 2.6 Hz, 1H), 7.31 (d, J=
F yridin-3-yl)propan-2 8.3 Hz, 1H), 7.14-7.08 (m, 84 ) N citrate -yl)pyrrolidin-3-y1) 473 2H), 3.91-3.75 (m, 4H), methyl)-3-ethyl-5,6-difl ¨r 3.46-3.26 (m, 4H), 3.13 (m, uoro-1,3-dihydro -2H-benzo[dlimidaz 1H), 2.91 (m, 1H), 2.75-2.64 ol-2-one citarte (m, 6H), 2.47 (s, 3H), 1.96 (m, 1H), 1.80 (m, 1H), 1.70 (d, J= 3.2 Hz, 6H), 1.18 (t, J
= 7.2 Hz, 3H), 1.08 (t, J= 7.0 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 9.04 (s, 1H), 8.60 (d, J=
2.3 Hz, 1H), 8.42 (s, 1H), (R or 8.38 (d, J= 5.8 Hz, 1H), 8.01 S)-1-((3-(ethoxymet (dd, J= 8.2, 2.4 Hz, 1H), hyl)-1-(2-(6-methylp 7.76 (d, J= 5.7 Hz, 1H), 7.37 N yridin-3-yl)propan-2 85 394 (d, J= 8.2 Hz, 1H), 4.64-4.45 --) citrate -yl)pyrrolidin-3-y1) \/ (m, 2H), 3.38 (m, 2H), 3.13 methyl)-1H-imidazo [4,5-c1pyridine (m, 2H), 2.91 (m, 2H), citrate 2.99-2.80 (m, 4H), 2.76 (m, 2H), 2.56 (s, 3H), 1.97 (m, 1H), 1.60-1.58 (m, 7H), 1.17 (t, J= 7.0 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 8.64 (t, J= 3.0 Hz, 1H), 8.54 (t, J= 3.9 Hz, 1H), 8.02-7.96 (m, 1H), 7.88-7.79 (m, 1H), 7.50-7.45 (m, 1H), 5-(2-((S or 7.43-7.34 (m, 2H), 7.15-7.11 Ni" R)-3-((R& (m, 1H), 6.88-6.83 (m, 1H), S)-ethoxy(pyridin-2- 6.75-6.71 (m, 1H), 4.49 (s, yl)methyl)-3-(2-(thi 0.5H), 4.47 (s, 0.5H), 3.73 (d, s-- ophen-2-yl)ethyl)pyr J= 11.4 Hz, 0.5 H), 3.46 (d, J
rolidin-l-yl)propan- = 11.4 Hz, 0.5 H), 3.39-3.35 citrate N 2-y1)-2-methylpyridi (m, 2H), 3.30-3.25 (m, 1H), ne citrate 3.23-3.03 (m, 2H), 3.01-2.96 (m, 1H), 2.83-2.73 (m, 5H), 2.56 (m, 3H), 2.41-2.20 (m, 1H), 1.93-1.84 (m, 1H), 1.76 (m, 6H), 1.74-1.42 (m, 2H), 1.17-1.06 (m, 3H) 1H NMR (300 MHz, Me0D):
6 8.72 (s, 1H), 8.06 (s, 1H), 7.42 (s, 1H), 7.20-7.18 (m, 5-(2-((R or S)-3-((S 4H), 7.09 (d, J= 4.8 Hz, 1H), or 6.82 (t, J= 3.3 Hz, 1H), 6.56 R)-isochroman-1-y1) (s, 1H), 4.11-4.05 (m, 1H), /
87 N s -3-(2-(thiophen-2-y1 447 3.61-3.50 (m, 2H), 3.10-3.05 citrate )ethyl)pyrrolidin-l-y (m ,1H), 2.98-2.86 (m, 2H), 1)propan-2-y1)-2-met 2.75 (q, J= 15.6 Hz, 4H), hylpyridine citrate 2.65-2.55 (m, 4H), 2.54-2.45 (m,4H), 2.20-2.00 (m, 2H), 1.83 (s, 6H), 1.70-2.55 (m, 2H) 1H NMR (300 MHz, Me0D):
6 8.65 (s, 1H), 7.98 (d, J=6.9 5-(2-((R or S)-3-((R Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.21-7.16 (m, 5H), 6.88 or 0 (t, J= 3.9 Hz, 1H), 6.75 (s, S)-isochroman-1 -y1) / 88 -3-(2-(thiophen-2-y1 1H), 4.08-4.06 (m, 1H), 3.56-3.46 (m, 2H), 3.16-3.08 citrate )ethyl)pyrrolidin-l-y (m, 1H), 2.85 (q, J= 15.5 Hz, 1)propan-2-y1)-2-met 4H), 2.58 (s, 6H), 2.19 (t, J=
hylpyridine citrate 7.5 Hz, 1H), 2.09-1.97 (m, 3H), 1.87-1.81 (m, 8H), 1.66-1.54 (m, 2H) 1H NMR (300 MHz, Me0D):
6 8.68 (s, 1H), 8.06 (s, 1H), 5-(2-((R or S)-3-((S 7.46 (s, 1H), 7.20 (m, 4H), 7.10 (t, J=5.7 Hz, 1H), 6.81 or 0 (m, 1H), 6.55 (m, 1H), R)-isochroman-l-y1) / 4.15-4.02 (m, 1H), 3.62-3.45 89 -3-(2-(thiophen-2-y1 461 (m, 4H), 3.21-2.95 (m, 2H), ) thyl)pyrrolidin-l-y = citrate 2.80 (q, J= 15.5 Hz, 4H), 1)butan-2-y1)-2-meth 2.58-2.49 (m, 6H), 2.47-2.25 ylpyridine citrate (m, 2H), 2.19-2.05 (m, 2H), 1.95-1.78 (m, 4H), 1.76-1.50 (m, 2H), 0.90-0.81 (m, 3H) 5-(2-((R or 1H NMR (300 MHz, Me0D):
oF, I \ S)-34(S&R)-1-etho 6 8.54 (m, 1H), 7.65-7.59 (m, xy-2,2,2-trifluoroeth 1H), 7.10 (d, J=7.8 Hz, 1H), 90 N y1)-3-(2-(5-fluorothi 473 6.33 (s, 1H), 6.23 (d, J= 1.8 ophen-2-yl)ethyl)pyr Hz, 1H), 4.01-3.80 (m, 1H), rolidin-l-yl)butan-2- 3.64-3.42 (m, 2H), 3.04-2.64 y1)-2-methylpyridine (m, 3H), 2.54 (s, 6H), 2.00-1.91 (m, 1H), 1.90-1.74 (m, 3H), 1.72-1.61 (m, 2H), 1.35 (s, 3H), 1.24-1.17 (m, 2H), 1.16-1.06 (m, 1H), 0.63 (t, J= 7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.98 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.40 (d, J= 5.8 Hz, 1H), 8.08-7.97 (m, 1H), 7.75 (d, J= 5.7 Hz, 1H), 7.39 1-(2-(3-(ethoxymeth y1)-1-(2-(6-methylpy (d, J= 8.5 Hz, 1H), 4.45 (t, J
o¨\
N) ridin-3-yl)propan-2- = 8.2 Hz, 2H), 3.48 (q, J=

citrate yl)pyrrolidin-3-yl)et 7.0 Hz, 3H), 3.39 (m, 2H), hyl)-1H-imidazo[4,5 3.24-3.12 (m, 2H), 3.10-3.02 -c]pyridine citrate (m, 1H), 2.81 (q, J= 15.6 Hz, 4H), 2.55 (s, 3H), 2.21-2.05 (m, 2H), 1.95-1.85 (m, 2H), 1.75 (s, 6H), 1.16 (t, J= 7.0 Hz, 3H).
1HNMR (500 MHz, Me0D):
6 8.66 (d, J= 2.1 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J=5.4 Hz, 1H), 8.02 (dd, J= 8.3, 2.4 Hz, 1H), 7.39 (d, J= 8.3 1-(2-(3-(ethoxymeth NH y1)-1-(2-(6-methylpy Hz, 1H), 7.17 (d, J=5.4 Hz, ridin-3-yl)propan-2- 1H), 3.94 (t, J= 7.7 Hz, 2H), 92 N) N yl)pyrrolidin-3-yl)et 424 3.46 (t, J= 7.1 Hz, 2H), 3.38 citarte hyl)-1,3-dihydro-2H
-imidazo[4,5-clpyrid (q, J= 9.2 Hz, 2H), 3.22-3.10 (m, 2H), 3.05 (d, J= 11.3 in-2-one citrate Hz, 1H), 2.90 (d, J= 11.4 Hz, 1H), 2.80 (q, J= 15.5 Hz, 4H), 2.55 (s, 3H), 2.01-1.82 (m, 4H), 1.74 (s, 6H), 1.14 (t, J= 7.0 Hz, 3H).
F3C 5-(2-((R or 1HNMR (300 MHz, Me0D):
/ S)-3-(2-ethoxy-1,1,1 68.51 (dd, J= 11.4, 1.8 Hz, 93 s F
,3,3,3-hexafluoropro 541 1H), 7.68-7.55 (m, 1H), 7.11 \---h pan-2-y1)-3-(2-(5-flu (d, J= 8.1 Hz, 1H), 6.38-6.26 orothiophen-2-yl)eth (m, 1H), 6.25 (d, J= 1.8 Hz, yl)pyrrolidin-l-yl)bu 1H), 4.01-3.82 (m, 2H), tan-2-y1)-2-methylp 3.11-2.75 (m, 4H), 2.55 (s, yridine 3H), 2.51-2.45 (m, 1H), 2.40-2.27 (m, 2H), 2.23-1.98 (m, 1H), 1.97-1.70 (m, 4H), 1.41-1.32 (m, 3H), 1.21-1.15 (m, 3H), 0.63 (t, J= 7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.61 (d, J= 2.1 Hz, 1H), 7.94 (m, 1H), 7.35 (d, J= 8.4 Hz, 1H), 7.19-7.08 (m, 4H), 5-(2-((R or 6.31 (d, J = 3.0 Hz, 1H),6.27 S)-3-(2-(5-fluorothio (t, J= 3.6 Hz, 1H), 4.15-4.02 phen-2-yl)ethyl)-3-(( (m, 1H), 3.55-3.49 (m, 1H), R or 94 / 465 3.20-3.11 (m, 2H), 3.07-3.01 S)-isochroman-1 -y1) (m, 1H), 2.98-2.88 (m, 2H), citrate pyrrolidin-l-yl)prop , 2.87-2.84 (m, 1H), 2.79 (q, J
1\1- an-2-y1)-2-methylpy = 15.6 Hz, 4H), 2.74-2.66 (m, ridine citrate 2H), 2.64-2.60 (m, 1H), 2.55 (s, 3H), 2.25-2.18 (m, 1H), 1.95-1.82 (m, 2H), 1.81-1.75 (m, 1H), 1.71 (m, 6H).
1HNMR (300 MHz, Me0D):
68.74 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.45 (d, J= 8.1 Hz, 5-(2-((R or 1H), 7.26-7.20 (m, 4H), S)-3-(2-(5-fluorothio 6.23-6.22 (m, 1H), 6.18 (d, J
0 phen-2-yl)ethyl)-3-(( = 2.7 Hz, 1H), 4.15-4.02 (m, / I S or 1H), 3.52-3.49 (m, 2H), S F R)-isochroman-1-y1) 3.15-3.05 (m, 1H), 2.79 (q, J
citrate pyrrolidin-l-yl)prop = 15.6 Hz, 4H), 2.74 (s, 3H), an-2-y1)-2-methylpy 2.54-2.43 (m, 2H), 2.38-2.28 ridine citrate (m, 2H), 2.20-2.08 (m, 2H), 1.87 (s, 6H), 1.80-1.75 (m, 1H), 1.65-1.60(m, 1H), 1.18 (t, J= 6.9 Hz, 3H).
5-(2-((R or S)-3-((R 1HNMR (300 MHz, Me0D):
\ or 6 8.69 (d, J= 2.1 Hz, 1H), I s F S)-ethoxy(phenyl)m 8.04 (d, J= 8.1 Hz, 1H), 96 LN citrate ethyl)-3-(2-(5-fluoro 481 7.52-7.47 (m, 1H), 7.40-7.34 thiophen-2-yl)ethyl) (m, 3H), 7.26 (d, J= 6.9 Hz, -pyrrolidin-l-yl)buta 1H), 7.22 (t, J=3.9 Hz, 1H), n-2-y1)-2-methylpyri 6.37 (d, J= 3.9 Hz, 1H), 6.28 dine citrate (m, 1H), 4.39 (m, 1H), 3.58-3.40 (m, 2H), 3.30-3.12 (m, 4H), 3.11-2.93 (m, 1H), 2.79 (q, J= 15.6 Hz, 4H), 2.78-2.70 (m, 3H), 2.60 (d, J
= 6.3 Hz, 3H), 2.28-2.20 (m, 1H), 2.10-2.00 (m, 1H), 1.83 (m, 3H), 1.75-1.62 (m, 1H), 1.58 (m, 1H), 1.03 (t, J= 7.2 Hz, 3H), 0.82 (t, J= 6.9 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.75 (s, 1H), 8.09 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 5-(2-((R or S)-3-((R 1H), 7.40-7.34 (m, 3H), 7.24 or (d, J= 6.3 Hz, 2H), 6.37 (s, 0 S)-ethoxy(phenyl)m 1H), 6.29 (t, J=2.9 Hz, 1H), / ethyl)-3-(2-(5-fluoro 4.40 (s, 1H), 3.56-3.50 (m, F thiophen-2-yl)ethyl) 1H), 3.49-3.38 (m, 3H), citrate pyrrolidin-l-yl)prop 3.28-3.22 (m, 2H), 2.98-2.90 an-2-y1)-2-methylpy (m, 2H), 2.79 (q, J= 15.6 Hz, ridine citrate 4H), 2.60 (s, 3H), 2.32-2.21 (m, 1H), 2.08-1.97 (m, 1H), 1.88 (m, 6H), 1.70-1.52 (m, 2H), 1.03 (t, J= 6.9 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 8.70(d, J= 1.8 Hz, 1H), 8.03 (m, 1H), 7.43 (d, J= 8.1 Hz, 1H), 7.35-7.28 (m, 5H), 5-(2-((R or S)-3-((S
6.37 (t, J= 3.3 Hz, 1H), or ¨\o R)-ethoxy(phenyl)m 6.30-6.28 (m, 1H), 4.40 (s, 1H), 3.47-3.40 (m, 2H), / I ethy1)-3-(2-(5-fluoro 98 467 3.25-3.15 (m, 2H), 3.08-2.90 F thiophen-2-yl)ethyl) ¨r citrate pyrrolidin-l-yl)prop (m, 2H), 2.79 (q, J= 15.6 Hz, 4H), 2.75-2.65 (m, 2H), 2.59 an-2-y1)-2-methylpy (s, 3H), 2.38-2.30 (m, 1H), ridine citrate 2.15-1.92 (m, 1H), 1.84 (m, 6H), 1.70-1.62 (m, 1H), 1.58-1.49(m, 1H), 1.11 (t, J=
7.2 Hz, 3H).

1HNMR (300 MHz, Me0D):
6 8.67 (d, J= 1.8 Hz, 1H), 8.03 (dd, J= 8.3, 2.3 Hz, 1H), 7.40 (d, J= 8.3 Hz, 1H), 1-(2-(3-(ethoxymeth 7.11 (t, J= 8.5 Hz, 1H), 7.01 y1)-1 -(2-(6-methylpy NH ridin-3-yl)propan-2- (t, J= 8.5 Hz, 1H), 3.85 (t, J
- ¨\ N
99 yl)pyrrolidin-3-yl)et = 7.8 Hz, 2H), 3.46 (m, 3H), 41t, F hyl)-5,6-difluoro-1,3 3.38 (m, 2H), 3.24-3.15 (m, F
citrate -dihydro-2H-benzo[ 2H), 3.08 (d, J= 11.4 Hz, dlimidazol-2-one 1H), 2.91 (d, J=11.7 Hz, citrate 1H), 2.80 (q, J= 15.5 Hz, 4H), 2.56 (s, 3H), 1.95-1.83 (m, 3H), 1.77 (s, 6H), 1.14 (t, J= 7.0 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 8.68 (s, 1H), 8.04 (d, J=
8.9 Hz, 1H),7.41 (d, J = 8.3 Hz, 1H), 7.20 (ddd, J= 16.9,
10.0, 6.9 Hz, 2H), 3.89 (t, J=
1-(2-(3-(ethoxymeth 7.5 Hz, 2H), 3.67 (d, J= 7.5 y1)-1 -(2-(6-methylpy ¨\00 '"5-4 ridin-3-yl)propan-2- Hz, 2H), 3.46 (q, J= 7.0 Hz, yl)pyrrolidin-3-yl)et 2H), 3.36 (m, 2H), 3.22 (m, F 515 hyl)-5,6-difluoro-3-i 2H), 3.11 (d, J= 11.5 Hz, F citrate sobuty1-1,3-dihydro-N 1H), 2.96 (d, J= 11.7 Hz, 2H-benzo[d]imidazo 1H), 2.80 (q, J= 15.5 Hz, 1-2-one citrate 4H), 2.56 (s, 3H), 2.19-2.08 (m, 1H), 2.01-1.82 (m, 4H), 1.79 (s, 6H), 1.14 (t, J= 7.0 Hz, 3H), 0.93 (d, J= 4.8 Hz, 6H).
1HNMR (300 MHz, Me0D):
1-(2-(3-(ethoxymeth 6 8.65 (s, 1H), 8.00(d, J=
y1)-1 -(2-(6-methylpy ridin-3-yl)propan-2- 6.2 Hz, 1H), 7.38 (d, J= 8.1 ¨O
yl)pyrrolidin-3-yl)et Hz, 1H), 7.24 (dd, J= 10.1, F hyl)-3-ethyl-5,6-difl 6.9 Hz, 1H), 7.15 (dd, J=
F citrate uoro-1,3-dihydro-2H
10.1, 7.0 Hz, 1H), 3.96-3.84 -benzo[dlimidazol-2 (m, 4H), 3.46 (q, J= 6.9 Hz, -one citrate 3H), 3.37 (s, 2H), 3.14 (m, 2H), 3.02 (m, 1H), 2.80 (q, J
= 15.5 Hz, 4H), 2.55 (s, 3H), 1.97-1.78 (m, 4H), 1.73 (s, 6H), 1.27 (t, J= 7.1 Hz, 3H), 1.14 (t, J= 7.0 Hz, 3H).
IHNMR (300 MHz, Me0D):
6 8.46 (d, J=5.2 Hz, 2H), 7.45 (s, 2H), 7.13 (dd, J=
5.2, 1.2 Hz, 1H), 6.87 (dd, J
= 5.2, 3.4 Hz, 1H), 6.78 (d, J
0 (S)-4-((3-(ethoxyme = 3.4 Hz, 1H), 3.66 (s, 2H), thyl)-3-(2-(thiophen-3.49 (q, J= 7.0 Hz, 2H), 3.34 2-yl)ethyl)pyrrolidin 331 H3PO4 (d, J= 3.5 Hz, 2H), 2.81 (t, J
-1-yl)methyl)pyridin e H3PO4 salt = 7.8 Hz, 2H), 2.63 (q, J=
7.0 Hz, 2H), 2.56 (d, J= 9.6 Hz, 1H), 2.34 (d, J= 9.6 Hz, 1H), 1.86 (m, 2H), 1.68 (t, J
= 6.9 Hz, 2H), 1.18 (t, J=7.0 Hz, 3H).
IHNMR (300 MHz, Me0D):
6 8.68 (s, 1H), 8.56 (s, 1H), 8.05 (m, 1H), 7.84 (m, 1H), 7.53-7.31 (m, 3H), 6.43-6.32 (m, 1H), 6.31-6.22 (m, 1H), 5-(2-((R or 4.47 (m, 1H), 3.79 (d, J=
S)-34(S&R)-ethoxy / \ 11.7 Hz, 1H), 3.51 (d, J=
-N (pyridin-2-yl)methyl
11.5 Hz, 1H), 3.25-3.15 (m, )-3-(2-(5-fluorothiop 103 / I 468 1H), 3.08 (d, J= 11.4 Hz, N S F hen-2-yl)eihyl)pyrro citrate lidin-1-yl)propan-2-H), 3.02-2.87 (m, 2H), 2.79 N y1)-2-methylpyridine (q, J= 15.5 Hz, 4H), citrate 2.70-2.63 (m, 1H), 2.58 (s, 3H), 2.42-2.23 (m, 1H), 2.12-1.89 (m, 1H), 1.82 (s, 6H), 1.79-1.59 (m, 2H), 1.52-1.36 (m, 1H), 1.18-1.01 (m, 3H).

111 NMR (300 MHz, Me0D):
68.64 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.45 (d, J= 8.1 Hz, 5-(2-((R or S)-3-((S 1H), 6.41 (m, 1H), 6.30 (m, or 1H), 3.64-3.57 (m, 1H), I F R)-1-ethoxyethyl)-3- 3.50-3.38 (m, 2H), 3.26-3.07 104 citrate (2-(5-fluorothiophen (m, 4H), 2.75 (q, J= 15.6 Hz, -2-yl)ethyl)pyrrolidi 419 4H), 2.71-2.61 (m, 2H), 2.57 n-1-yl)butan-2-y1)-2 (s, 3H), 2.53-2.44 (m, 1H), -methylpyridine 2.21-2.11 (m, 1H), 2.07-2.00 citrate (m, 1H), 1.80 (s, 3H), 1.76-1.57 (m, 3H), 1.13-1.02 (m, 6H), 0.78 (t, J= 7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
68.65 (s, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 8.1 Hz, 5-(2-((R or S)-3-((R
1H), 6.41 (d, J=3.9 Hz, 1H), or 6.30 (m, 1H), 3.64-3.56 (m, \ F S)-1-ethoxyethyl)-3-1H), 3.50-3.42 (m, 2H), (2-(5-fluorothiophen 105 419 3.22-3.08 (m, 2H), 2.77 (q, J
citrate -2-yl)ethyl)pyrrolidi n-1-yl)butan-2-y1)-2 = 15.6 Hz, 4H), 2.68-2.62 (m, 2H), 2.56 (s, 3H), 2.55-2.47 -methylpyridine (m, 2H), 2.07-2.00 (m, 2H), citrate 1.82 (s, 6H), 1.75-1.69 (m, 1H), 1.08-0.99 (m, 6H), 0.80 (t, J= 7.2 Hz, 3H) 1HNMR (300 MHz, Me0D):
6 8.53 (d, J= 1.8 Hz, 1H), (S or 7.85 (dd, J= 8.1, 2.1 Hz, 1H), 0 N¨\ R)-4-((3-(2-(5-fluor 7.25 (d, J= 8.1 Hz, 1H), 6.38 ) \ othiophen-2-yflethyl (t, J= 3.3 Hz, 1H), 6.28 (m, 1,1 )-1-(2-(6-methylpyri 432 1H), 3.63 (t, J= 4.5 Hz, 4H), din-3-yl)propan-2-y1 2.68-2.58 (m, 4H), 2.52 (S, )pyrrolidin-3-yl)met 3H), 2.50-2.38 (m, 6H), hyl)morpholine 2.36-2.28 (m, 2H), 1.82-1.70 (m, 2H), 1.66-1.54 (m, 2H), 1.42 (s, 6H) 107 (S or 507 111 NMR (300 MHz, Me0D):
R)-1-ethy1-34(3-(24 6 8.59 (s, 1H), 7.90 (s, 1H), 5-fluorothiophen-2- 7.30 (t, J=5.1 Hz, 1H), 7.17 N S F yflethyl)-1-(2-(6-me (d, J= 18.9 Hz, 4H), 6.43 (s, carate thylpyridin-3-yl)pro 1H), 6.29 (s, 1H), 3.99 (d, J=
pan-2-yl)pyrrolidin- 4.0 Hz, 4H), 3.14-3.05 (m, 3-yl)methyl)-1,3-dih 1H), 2.98 (s, 2H), 2.90-2.68 ydro-2H-benzo[d]im (m, 5H), 2.52 (d, J= 3.3 Hz, idazol-2-one citrate 3H), 2.07-1.95 (m, 1H), 1.87-1.77 (m, 3H), 1.65-1.55 (m, 6H), 1.35-1.29 (m, 5H).
1HNMR (300 MHz, Me0D):
6 8.70 (s, 1H), 8.06 (d, J=
7.8 Hz, 1H), 7.43 (d, J= 8.3 (R or Hz, 1H), 6.43 (s, 1H), 3.43 (31 / S)-5-(2-(3-(2-(4,5-di (q, J= 6.6 Hz, 2H), 3.18 (d, J
methylthiophen-2-y1 = 11.8 Hz, 1H), 2.96 (d, J=
108 )ethyl)-3-(ethoxymet 401 citrate 11.8 Hz, 1H), 2.80 (q, J=
hyl)pyrrolidin-l-yl)p 15.5 Hz, 4H), 2.70-2.59 (m, ropan-2-y1)-2-methy 1pyridine citrate 4H), 2.57 (s, 3H), 2.24 (s, 3H), 2.09-1.91 (m, 5H), 1.90-1.67 (m, 10H), 1.12 (t, J
= 6.9 Hz, 3H).
1HNMR (300 MHz, Me0D):
6 8.63 (d, J= 1.8 Hz, 1H), (R or 8.00 (dd, J= 8.1, 2.4 Hz, 1H), S)-N-((3-(2-(5-fluor \ 7.36 (d, J= 8.1 Hz, 1H), 6.43 othiophen-2-yl)ethyl / (t, J= 3.6 Hz, 1H), 6.29 (dd, J
s F )-1-(2-(6-methylpyri 109 440 = 3.9, 2.1 Hz, 1H), 3.12-3.02 citrate din-3-yl)propan-2-y1 (m, 4H), 3.01-2.95 (m, 1H), )pyrrolidin-3-yl)met 2.94 (s, 3H), 2.77 (q, J= 15.6 hyl)methanesulfona Hz, 4H), 2.72-2.64 (m, 3H), mide citrate 2.54 (s, 3H), 1.92-1.75 (m, 4H), 1.74 (s, 6H) 1HNMR (300 MHz, Me0D):
68.67 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.72 (d, J= 8.1 Hz, (R or 2H), 7.39 (t, J= 8.4 Hz, 3H), S)-N-((3-(2-(5-fluor othiophen-2-yl)ethyl 6.40 (t, J= 3.6 Hz, 1H), 6.27 (dd, J= 3.6, 2.1 Hz, 1H), )-1-(2-(6-methylpyri 110 / 516 3.32-3.30 (m, 3H), 3.29-3.18 S F din-3-yl)propan-2-y1 (m, 2H), 3.15-3.05 (m, 1H), )pyrrolidin-3-yl)met 2.90-2.80 (m, 3H), 2.75 (q, J
hyl)-4-methylbenzen = 15.6 Hz, 4H), 2.65-2.60 (m, esulfonamide citrate 1H), 2.55 (s, 3H), 2.42 (s, 3H), 1.95-1.82 (m, 2H), 1.72 (s, 6H) 111 (S or 520 tH NMR (300 MHz, Me0D):
R)-4-fluoro-N-((3-(2 68.65 (s, 1H), 8.03 (d, J=7.9 -(5-fluorothiophen-2 -yl)ethyl)-1-(2-(6-m Hz, 1H), 7.90 (dd, J= 8.7, 4.9 Hz, 2H), 7.49-7.24 (m, 3H), c),s,s'N
ethylpyridin-3-yl)pr 6.50-6.37 (m, 1H), 6.35-6.22 N s F opan-2-yl)pyrrolidin (m, 1H), 3.20-2.99 (m, 3H), citrate -3-yl)methyl)benzen 2.95-2.69 (m, 8H), 2.67-2.50 esulfonamide citrate (m, 5H), 1.87-1.68 (m, 9H).
tH NMR (300 MHz, Me0D):
6 8.61 (s, 1H), 8.00(d, J=
(S & R)-5-((R or 8.1 Hz, 1H), 7.36 (d, J = 8.0 S)-3-(2-(5-fluorothio Hz, 1H), 6.44 (t, J= 3.4 Hz, oo phen-2-yl)ethyl)-1-( / \ 1H), 6.30 (dd, J=3.7, 2.1 112 S F 2-(6-methylpyridin- 418 Hz, 1H), 4.88-4.70 (m, 1H), citrate 3-yl)propan-2-yl)pyr rolidin-3-yl)oxazolid 3.69-3.42 (m, 2H), 2.98-2.61 in-2-one citrate (m, 10H), 2.54 (s, 3H), 1.97-1.68 (m, 4H), 1.61 (s, 6H).
tH NMR (300 MHz, Me0D):
6 8.43 (s, 1H), 7.79 (d, J=
(R or 8.3 Hz, 1H), 7.34-7.23 (m, 11 S)-5-(2-(3-(2-(5-fluo 3H), 6.36-6.29 (m, 1H), HN-rothiophen-2-yl)ethy 1 6.28-6.23 (m, 1H), 3.15 (m, 13 1)-3-(1H-imidazol-2- 399 F 1H), 3.05-2.95 (m, 2H), yl)pyrrolidin-l-yl)pr citrate 2.93-2.73 (m, 5H), 2.57-2.45 N opan-2-y1)-2-methyl pyridine citrate (m, 5H), 2.41-2.29 (m, 1H), 2.24-2.01 (m, 3H), 1.51 (d, J
= 7.7 Hz, 6H).
tH NMR (300 MHz, Me0D):
6 8.55 (d, J= 1.9 Hz, 1H), (R or eN 7.92 (dd, J= 8.3, 2.3 Hz, S)-5-(2-(3-(2-(5-fluo rothiophen-2-yl)ethy 1H), 7.32 (d, J= 8.3 Hz, 1H), 1)-3-(1-methyl-1H-i 7.16 (d, J= 1.3 Hz, 1H), 7.04 midazol-2-yl)pyrroli (d, J=1.2 Hz, 1H), 6.33-6.18 I citrate din-1-yl)propan-2-y1 (m, 2H), 3.74 (s, 3H), 3.05 )-2-methylpyridine (m, 2H), 2.90-2.72 (m, 5H), citrate 2.53 (s, 3H), 2.50-2.43 (m, 1H), 2.40-2.08 (m, 6H), 1.56 (s, 6H).
1HNMR (300 MHz, Me0D):
6 8.56 (s, 1H), 8.01 (s, 1H), 7.66 (t, J= 4.1 Hz, 1H), 7.12 (d, J= 8.1 Hz, 1H), 6.28-6.19 (R or S)-5-(2-(3-(2-(5-fluo (m, 1H), 6.18 (d, J= 2.1 Hz, H N
rothiophen-2-yl)ethy 1H), 3.10-3.00 (m, 1H), 115 1)-3-(4H-1,2,4-triazo 400 2.99-2.85 (m, 1H), 2.80-2.68 F
1-3-yl)pyrrolidin-1-y (m, 1H), 2.66-2.55 (m, 2H), 1)propan-2-y1)-2-met N 2.53 (s, 3H), 2.50-2.42 (m, hylpyridine 1H), 2.40-2.25 (m, 2H), 2.15-2.05 (m, 1H), 1.98-1.88 (m, 1H), 1.45 (s, 3H), 1.45 (s, 3H).
1H NMR (300 MHz, Me0D):
6 8.73 (s, 1H), 8.09 (dd, J =
8.4, 1.7 Hz, 1H), 7.45 (d, J =
8.0 Hz, 1H), 6.46-6.39 (m, (R or >¨\ S)-5-(2-(3-((cyclopr 1H), 6.32-6.26 (m, 1H), o¨\
3.40-3.34 (m, 4H), 3.27-3.32 N) opylmethoxy)methyl )-3-(2-(5-fluorothiop (m, 3H), 3.00 (d, J= 12.2 hen-2-yl)ethyl)pyrro Hz, 1H), 2.82 (q, J = 15.6 ¨r citrate N%= lidin-1-yl)propan-2- Hz, 4H), 2.66 (t, J = 8.0 Hz, y1)-2-methylpyridine 2H), 2.57 (s, 3H), 2.06-1.99 citrate (m, 1H), 1.93-1.83 (m, 8H), 1.79 (d, J= 8.3 Hz, 1H), 1.02-0.89 (m, 1H), 0.56-0.46 (m, 2H), 0.22-0.13 (m, 2H).
1H NMR (300 MHz, Me0D):
6 8.61 (s, 1H), 7.98 (d, J=
(R or 7.3 Hz, 1H), 7.36 (d, J = 8.5 S)-3-(2-(5-fluorothio Hz, 1H), 6.43-6.36 (m, 1H), phen-2-yl)ethyl)-1-( s F 6.31-6.25 (m, 1H), 3.05-2.94 117 2-(6-methylpyridin- 376 3-yl)propan-2-yl)pyr (m, 2H), 2.81 (q, J = 15.5 citrate N rolidine-3-carboxam Hz, 4H), 2.68 (m, 1H), ide citrate 2.62-2.57 (m, 1H), 2.55 (s, 3H), 2.42-2.28 (m, 1H), 2.16-2.00 (m, 2H), 1.97-1.72 (m, 3H), 1.64 (s, 6H).
1HNMR (500 MHz, Me0D):
6 8.65 (d, J= 2.1 Hz, 1H), 8.03 (d, J= 8.3 Hz, 1H), 7.39 (d, J= 8.3 Hz, 1H), 7.30 (s, (R or 1H), 6.40 (t, J=3.6 Hz, 1H), S,E)-3-(2-(5-fluorot I F hiophen-2-yl)ethyl)-6.28 (dd, J = 3.9, 2.1 Hz, s 1-(2-(6-methylpyridi 1H), 3.78 (s, 3H), 3.36-3.32 N' n-3-yl)propan-2-yl)p yrrolidine-3-carbald (m, 1H), 3.24-3.15 (m, 1H), 3.05 (m, 1H), 2.93-2.88 (m, citrate ehyde 0-methyl 1H), 2.81 (q, J= 15.5 Hz, oxime citrate 4H), 2.69-2.57 (m, 2H), 2.56 (s, 3H), 2.24-2.17 (m, 1H), 1.97-1.89 (m, 2H), 1.89-1.82 (m, 1H), 1.72 (s, 6H).
1HNMR (300 MHz, Me0D):
6 8.51 (s, 1H), 7.87 (dd, J=
(S or OS R)-((3-(2-(5-fluoroth 5.7, 2.4 Hz, 1H), 7.26 (d, J=
=_o HN
\ F iophen-2-yl)ethyl)-1 8.1 Hz, 1H), 6.42 (s, 1H), 119 -(2-(6-methylpyridin 441 6.28 (t, J= 3.0 Hz, 1H), 3.04 -3-yl)propan-2-yl)py (s, 2H), 2.78-2.51 (m, 5H), rrolidin-3-yl)methyl) 2.50 (s, 3H), 2.34 (m, 1H), sulfamoyl amine 1.80-1.71 (m, 3H), 1.68-1.51 (m, 1H), 1.30 (s, 6H) 120 (S or R)- 518 1HNMR (300 MHz, Me0D):
((3-(2-(5-fluoro-thio 6 8.63 (s, 1H), 8.59-8.51 (m, phen-2-yl)ethyl)-1-( 1H), 7.99 (d, J= 8.5 Hz, 1H), 2-(6-methylpyridin-7.78 (t, J= 7.6 Hz, 1H), 7.48 3-yl)propan-2-yl)pyr (dd, J= 22.1, 7.7 Hz, 1H), rolidin-3-y1)(pyridin H2N / 0 -2-yl)methyl)sulfam 7.41-7.26 (m, 2H), 6.40-6.34 oyl amine (m, 1H), 6.28 (t, J= 3.1 Hz, / I
N S F 1H), 4.57 (d, J= 15.3 Hz, citrate 1H), 3.52 (d, J= 10.4 Hz, 1H), 2.96-2.75 (m, 7H), 2.56 (s, 3H), 2.33-2.28 (m, 1H), 1.85-1.75 (m, 1H), 1.71 (d, J
= 4.1 Hz, 6H), 1.58-1.43 (m, 2H).

121 (S or R)- 469 IHNMR (300 MHz, Me0D):
((3-(2-(5-fluorothiop 6 8.64 (s, 1H), 8.01 (d, J=
hen-2-yl)ethyl)-1-(2-0+0 7.5 Hz, 1H), 7.38 (d, J= 8.1 HN (6-methylpyridin-3-/ s\ Hz, 1H), 6.43 (s, 1H), 6.29 yl)propan-2-yl)pyrro lidin-3-yl)methyl)sul (s, 1H), 3.11-3.00 (m, 5H), citrate famoyl dimethyl 2.91-2.61 (m, 14H), 2.55 (s, amine 3H), 1.95-1.74 (m, 3H), 1.61 (s, 6H).
122 (R or 535 IHNMR (300 MHz, Me0D):
S)-((3-(2-(5-fluoroth 6 8.65 (d, J= 2.3 Hz, 1H), iophen-2-yl)ethyl)-1 8.04 (dd, J= 8.7, 2.3 Hz, -(2-(6-methylpyridin 1H), 7.40 (d, J= 8.2 Hz, 1H), -3-yl)propan-2-yl)py 7.22 (dd, J= 8.9, 4.7 Hz, F rrolidin-3-yl)methyl) sulfamoyl 2H), 7.04 (t, J= 8.5 Hz, 2H), NH
0-+0 HN, 4-fluorophenylamin 6.36 (d, J= 3.6 Hz, 1H), 6.27 e citrate (dd, J= 3.9, 2.1 Hz, 1H), citrate 3.18 (t, J= 7.0 Hz, 2H), 3.09 (d, J= 11.6 Hz, 1H), 2.98 (s, 2H), 2.92-2.69 (m, 5H), 2.63-2.49 (m, 5H), 1.89-1.79 (m, 2H), 1.75 (s, 6H), 1.71-1.64 (m, 2H).
123 (R or IHNMR (300 MHz, Me0D):
S)-((3-(2-(5-fluoroth 6 8.58 (s, 1H), 7.93 (d, J=
iophen-2-yl)ethyl)-1 8.1 Hz, 1H), 7.35 (d, J= 7.9 -(2-(6-methylpyridin HN Hz, 1H), 7.10 (s, 4H), 6.33 ..0 -s- -3-yl)propan-2-yl)py H`N (s, 1H), 6.26 (s, 1H), 2.95 (s, rrolidin-3-yl)methyl) / I
N SF sulfamoyl 3H), 2.89-2.69 (m, 5H), ¨(citrate 4-methylphenyl 2.62-2.49 (m, 6H), 2.26 (s, amine 3H), 1.79-1.69 (m, 5H), 1.60 (s, 6H).
124 ci (R or 531 IHNMR (300 MHz, Me0D):
S)-((3-(2-(5-fluoroth 6 8.60 (s, 1H), 7.96 (d, J=
HN 0C1 iophen-2-yl)ethyl)-1 n-ss, 8.5 Hz, 1H), 7.61 (d, J= 8.8 -/HsN
-(2-(6-methylpyridin / Hz, 1H), 7.49 (d, J= 2.4 Hz, NSNF -3-yl)propan-2-yl)py rrolidin-3-yl)methyl) 1H), 7.33 (dd, J= 19.1, 8.4 Exact Mass: 584.12 sulfamoyl Hz, 2H), 6.36 (s, 1H), tPSA: 73.8 CLogP: 6.67 2,4-dichloro phenyl 6.31-6.24 (m, 1H), 3.05-2.98 amine (m, 3H), 2.89-2.73 (m, 6H), 2.66-2.57 (m, 3H), 2.55 (s, 3H), 1.83-1.70 (m, 4H), 1.64 (s, 6H).
125 (S or 456 1H NMR (300 MHz, Me0D):
R)-4-methyl-N-((1-( 6 8.63 (s, 1H), 8.57 (d, J=
pyridin-3-ylmethyl)-4.9 Hz, 1H), 7.99 (d, J= 7.9 3-(2-(thiophen-2-y1) Hz, 1H), 7.74 (d, J= 8.0 Hz, 0 ethyl)pyrrolidin-3-y1 )methyl)benzenesulf 2H), 7.52 ¨7.48 (m, 1H), O=y=o onamide citrate 7.38 (d, J= 7.9 Hz, 2H), HN I s\ 7.19-7.11 (m, 1H), 6.88 (dd, J=5.1, 3.5 Hz, 1H), 6.81 (d, N citrate J= 3.4 Hz, 1H), 4.19 (s, 2H), N 3.23-3.11 (m, 3H), 2.91 (d, J
= 7.0 Hz, 2H), 2.88-2.69 (m, 7H), 2.42 (s, 3H), 1.99-1.81 (m, 4H).
126 (S or 526 1H NMR (300 MHz, Me0D):
R)-N-((3-(2-(4,5-di 6 8.65 (s, 1H), 8.02 (d, J=
methylthiophen-2-y1 8.3 Hz, 1H), 7.71 (d, J= 8.0 )ethyl)-1-(2-(6-meth 4o ylpyridin-3-yl)propa Hz, 2H), 7.39 (t, J= 6.9 Hz, 3H), 6.41 (s, 1H), 3.22-3. 15 -s- n-2-yl)pyrrolidin-3-0'H`N
/ I yflmethyl)-4-methyl (m, 2H), 3.10-3.06 (m, 1H), N S benzenesulfonamide 2.89-2.71 (m, 8H), 2.62-2.53 citrate citrate (m, 5H), 2.43 (s, 3H), 2.23 N
(s, 3H), 2.02 (s, 3H), 1.87-1.83 (m, 1H), 1.77-1.69 (m, 8H).
127 (S or 510 1H NMR (300 MHz, Me0D):
R)-N-((3-(4-fluorop 6 8.65 (s, 1H), 8.02 (d, J=
henethyl)-1-(2-(6-m 8.1 Hz, 1H), 7.73 (d, J= 8.0 1101 ethylpyridin-3-yl)pr Hz, 2H), 7.39 (d, J= 8.0 Hz, o==o opan-2-yl)pyrrolidin HN
F 3H), 7.20-7.11 (m, 2H), 6.95 -3-yl)methyl)-4-met hylbenzenesulfonam (t, J= 8.7 Hz, 2H), 3.15 (t, J
N citrate ide citrate >in...... = 5.8 Hz, 2H), 3.05 (d, J=
I , 11.0 Hz, 1H), 2.87-2.71 (m, N
7H), 2.55 (s, 3H), 2.51-2.44 (m, 2H), 2.43 (s, 3H), 1.90-1.79 (m, 2H), 1.74 (s, 6H), 1.70-1.59 (m, 2H).
(R or frN S)-5-(2-(3-(ethoxym N
I \ ethyl)-1-(2-(6-methy 128 s 1pyridin-3-yl)propan jr_0_ -2-yl)pyrrolidin-3-y1 )ethyl)thieno[3,4-blp yrazine (R or ii--"N S)-5-(2-(3-(ethoxym N
I \ F ethyl)-1-(2-(6-methy 129 (:) s 1pyridin-3-yl)propan 1:21_01_ -2-yl)pyrrolidin-3-y1 )ethyl)-7-fluorothien o[3,4-blpyrazine 1-((R or ¨N S)-1-(2-(6-methylpy o \ ridin-3-yl)propan-2-130 y1)-3-(2-(thiophen-2 N s.-- -yl)ethyl)pyrrolidin-3-y1)-3,4-dihydro-1 N H-pyrano[4,3-c]pyri dine F 5-(2-((3R or S)-3-(6-fluoroisochr o oman-1-y1)-3-(2-(thi 131 / ophen-2-yl)ethyl)pyr I
N s rolidin-l-yl)propan--r 2- 1 -2-meth 1 ridi Y ) Y PY
N ne 5-(2-((3R or FIN S)-3-((4,5-dihydro-1 ¨N
¨\ H-imidazol-2-y1)(eth \_c. oxy)methyl)-3-(2-(th ' 1 N S--- iophen-2-yl)ethyl)py -r rrolidin-l-yl)propan-N*\ 2-y1)-2-methylpyridi ne (R or H S)-5-(2-(3-(((4,5-dih Cydro-1H-imidazol-2-133 ni o yl)methoxy)methyl)-/ I
N s 3-(2-(thiophen-2-y1) ethyl)pyrrolidin-l-y1 N )propan-2-y1)-2-met hylpyridine 5-(2-((S or R)-3-((S
% or ¨\ R)-ethoxy(pyridin-3 134 \ (_ -Y1)methyl)-3-(2-(thi N s' 0phen-2-yl)eihyl)pyr I
rolidin-l-yl)propan--N 2-y1)-2-methylpyridi ne 5-(2-((S or R)-3-((S
or __ ¨\ N
R)-ethoxy(pyridin-2 135 \ ----.1.. -yl)methyl)-3-(2-(thi N \s-j- ophen-2-yl)ethyl)pyr ¨, rolidin-l-yl)propan-N 2-y1)-2-methylpyridi ne N 5-(2-((3R or / ) S)-3-(ethoxy(pyridin ¨\
o -4-yl)methyl)-3-(2-(t 136 1-I hiophen-2-yl)ethyl)p N \S yrrolidin-l-yl)propa --( n-2-y1)-2-methylpyri N - dine (R or ¨\o S)-2-(2-(3-(ethoxym / I ethyl)-1-(2-(6-methy 137 N S N 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 N )ethyl)thieno[2,3-clp yridine (R or ¨\(:) S)-2-(2-(3-(ethoxym 138 ethyl)-1-(2-(6-methy N S
1pyridin-3-yl)propan N -2-yl)pyrrolidin-3-y1 )ethyl)thieno[3,2-clp yridine (R or ¨\o S)-6-(2-(3-(ethoxym N ethyl)-1-(2-(6-methy / I
139 N S N 1pyridin-3-yl)propan N -2-yl)pyrrolidin-3-y1 )ethyl)thieno[2,3-blp yrazine (R or F S)-5-(2-(3-(2-(4,5-di Tho /s\ F fluorothiophen-2-y1) 140 N ethyl)-3-(ethoxymet hyl)pyrrolidin-l-yl)p N ropan-2-y1)-2-methy 1pyridine (R or NC
____ S)-4-(2-(3-(ethoxym ----\o S ethyl)-1-(2-(6-methy 141 N 1pyridin-3-yl)propan ---- -2-yl)pyrrolidin-3-y1 tN-\ )ethyl)thiophene-3-c arbonitrile (R or F
____ S)-5-(2-(3-(ethoxym o S ethyl)-3-(2-(4-fluoro 142 N thiophen-3-yl)ethyl) ---- pyrrolidin-l-yl)prop t N\ an-2-y1)-2-methylpy ridine (R or F
S)-5-(2-(3-(ethoxym o / s\ ethyl)-3-(2-(4-fluoro N thiophen-2-yl)ethyl) pyrrolidin-l-yl)prop I
N an-2-y1)-2-methylpy ridine (R or CN
S)-5-(2-(3-(ethoxym ethyl)-1-(2-(6-methy 144 N 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)thiophene-3-c N
arbonitrile 1-((R or _N
S)-3-(2-(5-fluorothio \
phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-145 / SF 3-yl)propan-2-yl)pyr rolidin-3-y1)-3,4-dih ydro-1H-pyrano[4,3-N
c]pyridine 5-(2-((3R or S)-3-(6-fluoroisochr 0 oman-1-y1)-3-(2-(54 / luorothiophen-2-yl)e thyl)pyrrolidin-l-y1) propan-2-y1)-2-meth ylpyridine &N
5-(2-((3R or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-3-(i 147 / sochroman-l-yl)pyrr S F olidin-l-yl)propan-2 -y1)-2-methylpyridin HN/. 5-(2-((3R or S)-3-((4,5-dihydro-1 H-imidazol-2-y1)(eth \ oxY)methY0-3-(2-(5 -fluorothiophen-2-y1 )ethyl)pyrrolidin-l-y 1)propan-2-y1)-2-met hylpyridine (R or S)-5-(2-(3-(((4,5-dih N 0-\ ydro-1H-imidazol-2-) yl)methoxy)methyl)-N S
3-(2-(5-fluorothioph en-2-yl)ethyl)pyrroli din-l-yl)propan-2-y1 )-2-methylpyridine 5-(2-((S or R)-3-((R
( \ N or ¨/
¨\o S)-ethoxy(pyridin-3-150 / I yl)methyl)-3-(2-(5-fl N S F uorothiophen-2-yl)et Thr hyl)pyrrolidin-l-yl)p N ropan-2-y1)-2-methy 1pyridine 5-(2-((S or R)-3-((R
/ \
or -\ N
o S)-ethoxy(pyridin-2-CT yl)methyl)-3-(2-(5-fl 151 N s-"NF uorothiophen-2-yl)et --v-I
hyl)pyrrolidin-l-yl)p ropan-2-y1)-2-methy 1pyridine 5-(2-((S or R)-3-((R
/ N\
or ¨\o S)-ethoxy(pyridin-4-eI

yl)methyl)-3-(2-(5-fl N S F uorothiophen-2-yl)et hyl)pyrrolidin-l-yl)p N ropan-2-y1)-2-methy 1pyridine (S or R)-5-(2-(3-(ethoxym /
i ethyl)-3-((5-fluoroth S
153 N F iophen-2-yl)methyl) --- pyrrolidin-l-yl)prop \ / N an-2-y1)-2-methylpy ridine 5-(2-((3R or S)-3-(ethoxy(1-meth i=\
...--N ,N y1-1H-imidazol-2-y1 154 o ..----- I s\ F )methyl)-3-(2-(5-flu orothiophen-2-yl)eth )--Qii ¨ yl)pyrrolidin-l-yl)pr opan-2-y1)-2-methyl pyridine 8-((R or S)-3-(2-(5-fluorothio /=\
N ,N phen-2-yl)ethyl)-1-( 155 C I \
s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr 121-1¨C rolidin-3-y1)-5,6-dih N
ydro-8H-imidazo[2, 1-c][1,41oxazine 5-(2-((3R or S)-3-(ethoxy(1H-imi /=-\
HN ,N
dazol-2-yl)methyl)-3 I s\ F
156 o -(2-(5-fluorothiophe n-2-yl)ethyl)pyrrolid in-1-yl)propan-2-y1) -2-methylpyridine 7-((R or S)-3-(2-(5-fluorothio (> phen-2-yl)ethyl)-1-( c,N0 i \ F 2-(6-methylpyridin-s 3-yl)propan-2-yl)pyr r\-11-01¨ rolidin-3-y1)-5H,7H-imidazo[1,2-cloxazo 1-5-one 3-ethyl-5-((R or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( ool\l I \ F
158 s 2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr " rolidin-3-yl)oxazolid in-2-one (R or HO S \
\ S)-2-(1-(2-(6-methyl pyridin-3-yl)propan-N
2-y1)-3-(2-(thiophen N -2-yl)ethyl)pyrrolidi n-3-yl)propan-2-ol (R or CF
S)-1,1,1,3,3,3-hexafl HO , ` uoro-2-(1-(2-(6-met 160 N hylpyridin-3-yl)prop an-2-y1)-3-(2-(thiop ---)\/1 &N hen-2-yl)ethyl)pyrro lidin-3-yl)propan-2-ol CF3 s (R or S)-5-(2-(3-(1-ethoxy -2,2,2-trifluoroethyl) 161 -3-(2-(thiophen-2-y1 1 )ethyl)pyrrolidin-l-y 1)propan-2-y1)-2-met hylpyridine HO CF3 s¨(R or S)-2,2,2-trifluoro-1-( 1-(2-(6-methylpyridi 162 N n-3-yl)propan-2-y1)-3-(2-(thiophen-2-y1) 1 ethyl)pyrrolidin-3-y1 )ethan-l-ol OH (R or HO) S S)-1-(1-(2-(6-methyl pyridin-3-yl)propan-163 2-y1)-3-(2-(thiophen -2-yl)ethyl)pyrrolidi n-3-yl)ethane-1,2-di ol OH (R or Oj S)-2-ethoxy-2-(1-(2-(6-methylpyridin-3-164 yflprop an-2-y1)-3-(2 -(thiophen-2-yl)ethy 1)pyrrolidin-3-yfleth an-l-ol NH2 (R or S)-2-ethoxy-2-(1-(2-(6-methylpyridin-3-165 yflprop an-2-y1)-3-(2 -(thiophen-2-yl)ethy 1 1)pyrrolidin-3-yfleth an-1-amine (R or \ S)-5-(2-(3-(1,4-diox an-2-y1)-3-(2-(thiop hen-2-yl)ethyl)pyrro lidin-l-yl)propan-2-y1)-2-methylpyridine (-NH (R or 0 \ S)-2-(1-(2-(6-methyl 167 pyridin-3-yl)propan-2-y1)-3-(2-(thiophen -2-yl)ethyl)pyrrolidi n-3-yl)morpholine 5-(2-((R or F S)-3-((S)-ethoxyfluo romethyl)-3-(2-(5-fl I
168 N S F uorothiophen-2-yl)et hyl)pyrrolidin-l-yl)p N ropan-2-y1)-2-methy 1pyridine 5-(2-((R or F S)-3-((R)-ethoxyfluo o romethyl)-3-(2-(5-fl I
169 N s uorothiophen-2-yl)et hyl)pyrrolidin-l-yl)p ropan-2-y1)-2-methy 1pyridine (R or S)-5-(2-(3-(1-ethoxy cyclopropy1)-3-(2-(5 I
170 N S F -fluorothiophen-2-y1 )ethyl)pyrrolidin-l-y 1)propan-2-y1)-2-met hylpyridine ¨1 (R or 0-( S)-5-(2-(3-(2-ethoxy ) propan-2-y1)-3-(2-(5 s-171 F -fluorothiophen-2-y1 )ethyl)pyrrolidin-l-y 1)propan-2-y1)-2-met hylpyridine 2-ethoxy-2-((R or CN S)-3-(2-(5-fluorothio \-ON p2h-(e6n-2-yl)ethyl)-1-( -methylpyridin-3-yl)propan-2-yl)pyr ¨r 1\1*- rolidin-3-yl)acetonit rile NC (R or S)-2-((3-(2-(5-fluoro thiophen-2-yl)ethyl) 173 -1-(2-(6-methylpyrid in-3-yl)propan-2-y1) pyrrolidin-3-yl)meth oxy)acetonitrile (R or S)-5-(2-(3-(ethoxym ethyl)-1-(2-(6-methy I
174 / N S eN 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)thiophene-2-c arbonitrile (R or S)-(3-(2-(5-fluorothi H2N-e0 ophen-2-yl)ethyl)-1-S F (2-(6-methylpyridin-N
Thc 3-yl)propan-2-yl)pyr rolidin-3-yl)methyl carbamate (R or H2N-e S)-2-(3-(2-(5-fluorot o hiophen-2-yl)ethyl)-176 \¨esiF 1-(2-(6-methylpyridi n-3-yl)propan-2-yl)p yrrolidin-3-yl)propa n-2-y1 carbamate (R or S)-2-(3-(2-(5-fluorot HN-e hiophen-2-yl)ethyl)-¨c o 1-(2-(6-methylpyridi / I
N S F n-3-yl)propan-2-yl)p yrrolidin-3-yl)propa n-2-y1 isopropylcarbamate (R or S)-2-(3-(2-(5-fluorot HN4)0 hiophen-2-yl)ethyl)-1-(2-(6-methylpyridi /
178 N S F n-3-yl)propan-2-yl)p yrrolidin-3-yl)propa n-2-y1 phenylcarbamate (R or S)-difluoro(3-(2-(5-f 1-12N¨eo F F
/
luorothiophen-2-yl)e 179 I F thyl)-1-(2-(6-methyl N S
N pyridin-3-yl)propan-2-yl)pyrrolidin-3-y1) methyl carbamate (R or S)-difluoro(3-(2-(5-f FIN¨e F , 0 r luorothiophen-2-yl)e / I thyl)-1-(2-(6-methyl ¨I pyridin-3-yl)propan-N 2-yl)pyrrolidin-3-y1) methyl isopropylcarbamate (R or S)-difluoro(3-(2-(5-f HN4)0 F F luorothiophen-2-yl)e 0 181 thyl)-1-(2-(6-methyl / I
N S F pyridin-3-yl)propan-2-yl)pyrrolidin-3-y1) methyl phenylcarbamate (R or S)-1,1,1,3,3,3-hexafl N2N¨K/F 03c ,F3 uoro-2-(3-(2-(5-fluo rothiophen-2-yl)ethy I
N S F 1)-1-(2-(6-methylpyr N idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-y1 carbamate (R or S)-1,1,1,3,3,3-hexafl HN403C u3 uoro-2-(3-(2-(5-fluo rothiophen-2-yl)ethy 183 N S F 1)- 1-(2-(6-methylpyr ¨I. idin-3-yl)propan-2-y N 1)pyrrolidin-3-yl)pro pan-2-y1 isopropylcarbamate (R or S)-1,1,1,3,3,3-hexafl uoro-2-(3-(2-(5-fluo HN403C 184 ,F3 rothiophen-2-yl)ethy / 1)-1-(2-(6-methylpyr N S F
idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-y1 phenylcarbamate (S)-1-((R or H2N-e0_( S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 185 r\CP S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl carbamate (R)-1-((R or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 186 / I S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl carbamate (S)-1-((R or Hs-e S)-3-(2-(5-fluorothio ¨c 0 187 phen-2-yl)ethyl)-1-( N S F
/ I 2-(6-methylpyridin--I
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl isopropylcarbamate (R)-1-((R or HN-e0 S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 188 N 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl isopropylcarbamate (S)-1-((R or HN S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( S F
/ 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl phenylcarbamate (R)-1-((R or HN¨e S)-3-(2-(5-fluorothio o phen-2-yl)ethyl)-1-( 190 / 2-(6-methylpyridin-N F
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl phenylcarbamate (S)-fluoro((R or H2N¨e F S)-3-(2-(5-fluorothio o phen-2-yl)ethyl)-1-( 191 N I F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl carbamate (R)-fluoro((R or S)-3-(2-(5-fluorothio H2N¨eo phen-2-yl)ethyl)-1-( 192 2-(6-methylpyridin-N S"--NF
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl carbamate (S)-fluoro((R or ^ F S)-3-(2-(5-fluorothio ¨c 0 phen-2-yl)ethyl)-1-( 193 / I 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl isopropylcarbamate (R)-fluoro((R or S)-3-(2-(5-fluorothio ¨c^ 0 = phen-2-yl)ethyl)-1-( 194 / I 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl isopropylcarbamate (S)-fluoro((R or HN¨e F S)-3-(2-(5-fluorothio o phen-2-yl)ethyl)-1-( 195 / 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl phenylcarbamate (R)-fluoro((R or S)-3-(2-(5-fluorothio HN¨eo phen-2-yl)ethyl)-1-( 196 2-(6-methylpyridin-N F
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl phenylcarbamate (R)-2,2,2-trifluoro-1 H2N¨eo cF3 -((R or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl carbamate (S)-2,2,2-trifluoro-1-H2N¨e0 .zpF3 ((R or S)-3-(2-(5-fluorothio )--\ phen-2-yl)ethyl)-1-( 198 N s 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl carbamate (R)-2,2,2-trifluoro-1 cF3 -((R or HN¨e S)-3-(2-(5-fluorothio ) phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl isopropylcarbamate (S)-2,2,2-trifluoro-1-HN4 cF3 ((R or ¨Kso S)-3-(2-(5-fluorothio I phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl isopropylcarbamate (R)-2,2,2-trifluoro-1 HN40 cF3 -((R or 201 I S F S)-3-(2-(5-fluorothio N
phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl phenylcarbamate (S)-2,2,2-trifluoro-1-HN40 zcF3 ((R or S)-3-(2-(5-fluorothio / I 202 phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl phenylcarbamate 1-fluoro-1-((R or H2N¨eo phen-2-yl)ethyl)-1-( S)-3-(2-(5-fluorothio 203 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl carbamate 1-fluoro-1-((R or S)-3-(2-(5-fluorothio HN¨e CH3 0 F phen-2-yl)ethyl)-1-( 204 / I S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl isopropylcarbamate 1-fluoro-1-((R or HN¨eoCHS)-3-(2-(5-fluorothio / I phen-2-yl)ethyl)-1-( 205 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl phenylcarbamate 1,1,1-trifluoro-2-((R
or N2N¨eo ch&, S)-3-(2-(5-fluorothio / phen-2-yl)ethyl)-1-( s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-y1 carbamate 1,1,1-trifluoro-2-((R
or HN- CH3 S)-3-(2-(5-fluorothio e _c 0 CF3 phen-2-yl)ethyl)-1-( 207 1 I 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr N rolidin-3-yl)propan-2-y1 isopropylcarbamate 1,1,1-trifluoro-2-((R
or S)-3-(2-(5-fluorothio Hs40 CH 6F3 208 0 phen-2-yl)ethyl)-1-( / I S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr N rolidin-3-yl)propan-2-y1 phenylcarbamate 1-(1,2,2,2-tetrafluor H2N4 F o-1-((R or HN¨CF3 S)-3-(2-(5-fluorothio ( \ es---i phen-2-yl)ethyl)-1-( F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-isopropyl-3-(1,2,2, 2-tetrafluoro-1-((R
HN¨e F or \_ro S)-3-(2-(5-fluorothio 210 'SNF phen-2-yl)ethyl)-1-( ¨i- 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-pheny1-3-(1,2,2,2-t etrafluoro-1-((R or HN-E.01,1 F c3 S)-3-(2-(5-fluorothio 0 phen-2-yl)ethyl)-1-( / I

N S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr N
rolidin-3-yl)ethyl)ur ea isopropyl ((S)-1-((R
or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-iPr 0 \o4 3-yl)propan-2-yl)pyr HN
/ I rolidin-3-yl)ethyl)ca 212 NSF rbamate isopropyl ((lS)-1-(3-(2-(5-fluo rothiophen-2-yl)ethy 1)-1-(2-(6-methylpyr idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)eth yl)carbamate isopropyl ((R)-1-((R
iPr 0 or N ' H
S)-3-(2-(5-fluorothio F 213 I phen-2-yl)ethyl)-1-( S
2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate isopropyl ((R)-fluoro((R or 0¨(< S)-3-(2-(5-fluorothio 214 HN ' / phen-2-yl)ethyl)-1-( N S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) carbamate isopropyl ((S)-fluoro((R or iPr 0 04 F S)-3-(2-(5-fluorothio / phen-2-yl)ethyl)-1-( N S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) carbamate iPr õ0 pF3 isopropyl HN ((S)-2,2,2-trifluoro-1 S F -((R or S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate isopropyl 0R)-2,2,2-trifluoro-iPr, 0 1-((R or 0¨ CF3 Ft S)-3-(2-(5-fluorothio 217 N S F phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate isopropyl (R or ipr,c4H3c S)-(2-(3-(2-(5-fluoro cH3 thiophen-2-yl)ethyl) 218 \-0,F -1-(2-(6-methylpyrid in-3-yl)propan-2-y1) pyrrolidin-3-yl)prop an-2-yl)carbamate isopropyl (1,1,1-trifluoro-2-(( Pr R or i,o_Ff)3C c3 S)-3-(2-(5-fluorothio 219 phen-2-yl)ethyl)-1-( N S F
2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-yl)carbamate isopropyl (R or iPr,o40 F S)-(difluoro(3-(2-(5-HN¨F fluorothiophen-2-y1) 220 ethyl)-1-(2-(6-methy N S F
1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )methyl)carbamate isopropyl iPr \040 F
(1,2,2,2-tetrafluoro-1-((R or cF\-0,3 S)-3-(2-(5-fluorothio S F
phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate isopropyl (R or S)-(1,1,1,3,3,3-hexaf iPr, 0-((F3C
HN CF3 luoro-2-(3-(2-(5-fluo rothiophen-2-yl)ethy N F 1)-1-(2-(6-methylpyr idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-yl)carbamate phenyl ((R)-1-((R or Ph 0 so4 , S)-3-(2-(5-fluorothio HN phen-2-yl)ethyl)-1-( 223 / I 2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl ((S)-1-((R or Ph 0 S)-3-(2-(5-fluorothio HN phen-2-yl)ethyl)-1-( 224 / I S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl ((R)-fluoro((R or Ph 0 1)4 f S)-3-(2-(5-fluorothio HN
phen-2-yl)ethyl)-1-( 225 1\1 \SF 2-(6-methylpyridin-Th0 3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) carbamate phenyl ((S)-fluoro((R or Ph 0 F S)-3-(2-(5-fluorothio 226 / phen-2-yl)ethyl)-1-( S F
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) carbamate Ph, p 0-1( ,cF3 HN ' phenyl ((S)-2,2,2-trifluoro-1 227 / I S F -((R or N
S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl 0R)-2,2,2-trifluoro-Ph 0 b¨Ft CF3 1-((R or S)-3-(2-(5-fluorothio 228 l I phen-2-yl)ethyl)-1-( N S F
¨I
N 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl (R or Ph 0 `0_1-13c S)-(2-(3-(2-(5-fluoro HN¨CH3 thiophen-2-yl)ethyl) c \¨esiF -1-(2-(6-methylpyrid Th( N in-3-yl)propan-2-y1) ) pyrrolidin-3-yl)prop an-2-yl)carbamate phenyl (1-fluoro-1-((R or Ph 0 b4H3c S)-3-(2-(5-fluorothio FIN¨F
230 \_,-.1 phen-2-yl)ethyl)-1-( " ssNF 2-(6-methylpyridin--I
N 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl Ph (1,1,1-trifluoro-2-(( , 9 0-1(H3C
HN CF3 R or / I S)-3-(2-(5-fluorothio 231 N S F phen-2-yl)ethyl)-1-( IN 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-yl)carbamate phenyl (R or Ph 0 bINF S)-(difluoro(3-(2-(5-F fluorothiophen-2-y1) F
232 / I ethyl)-1-(2-(6-methy N S
¨I
N 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )methyl)carbamate phenyl (1,2,2,2-tetrafluoro-Ph 0 1-((R or F
HNICF3 S)-3-(2-(5-fluorothio 233 \¨a phen-2-yl)ethyl)-1-( F
2-(6-methylpyridin-Th() 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ca rbamate phenyl (R or Ph S)-(1,1,1,3,3,3-hexaf b¨H\NF3c cF3 luoro-2-(3-(2-(5-fluo /
234 rothiophen-2-yl)ethy S F 1)-1-(2-(6-methylpyr idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-yl)carbamate 235 (R or 404 IHNMR (300 MHz, Me0D):
S)-1-((3-(2-(5-fluoro 68.78 (s, 1H), 8.27 (d, J=6.6 H2N_r thiophen-2-yl)ethyl) Hz, 1H), 7.52 (d, J= 7.8 Hz, HN
-1-(2-(6-methylpyrid 1H), 6.46 (s, 1H), 6.32 (s, N S F in-3-yl)propan-2-y1) 1H), 3.11-2.99 (m, 2H), MCI, citrate pyrrolidin-3-yl)meth 2.94-2.76 (m, 7H), 2.71-2.55 yl)guanidine citrate (m, 5H), 2.05-1.90 (m, 2H), 1.88-1.72 (m, 9H).
(S or R)-1-((3-(2-(5-fluor H2N¨

othiophen-2-yl)ethyl 236 fN / I )-1-(2-(6-methylpyri din-3-yl)propan-2-y1 )pyrrolidin-3-yl)met hyl)urea 1-((R)-1-((R or H2N¨e S)-3-(2-(5-fluorothio HN ' / phen-2-yl)ethyl)-1-( 237 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-((S)-1-((R or S)-3-(2-(5-fluorothio HN
H2N4:3 phen-2-yl)ethyl)-1-( 238 s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-((R)-fluoro((R or H2N¨e S)-3-(2-(5-fluorothio HN phen-2-yl)ethyl)-1-( 239 / 1 S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) urea 1-((S)-fluoro((R or H2N¨ fN F S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( S F 2-(6-methylpyridin-N
3-yl)propan-2-yl)pyr rolidin-3-yl)methyl) urea 1-((S)-2,2,2-trifluoro or H2N¨e zg F3 S)-3-(2-(5-fluorothio HN
241 / phen-2-yl)ethyl)-1-( S F
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-((R)-2,2,2-trifluor H2N¨e cF3 o-1-((R or HN S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea (R or H2N¨fN cHFI3 S)-1-(2-(3-(2-(5-fluo rothiophen-2-yl)ethy 243 S F 1)- 1-(2-(6-methylpyr idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-yl)urea o 1-(1-fluoro-1-((R or H2N¨e cH3 HN¨F S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 244 N s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-(1,1,1-trifluoro-2-( H2N¨e cH3 (Ror FiNcF3 S)-3-(2-(5-fluorothio e s-3, phen-2-yl)ethyl)-1-( F 2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-yl)urea (R or S)-1-(difluoro(3-(2-( H2N¨FfN F F
5-fluorothiophen-2-246 yl)ethyl)-1-(2-(6-me N S F
thylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)urea (R or H2N¨ S)-1-(1,1,1,3,3,3-hex fN cF3cF3 afluoro-2-(3-(2-(5-fl e s3, uorothiophen-2-yl)et F hyl)-1-(2-(6-methylp yridin-3-yl)propan-2 -yl)pyrrolidin-3-yl)p ropan-2-yl)urea iPr 1-((R)-1-((R or FIN-1( S)-3-(2-(5-fluorothio HN ' /
phen-2-yl)ethyl)-1-( I
248 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -isopropylurea iPr\ 0 1-((S)-1-((R or HN¨N S)-3-(2-(5-fluorothio / I phen-2-yl)ethyl)-1-( 249 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -isopropylurea iPr\ 1-((R)-fluoro((R or H N S)-3-(2-(5-fluorothio HN
\_11 phen-2-yl)ethyl)-1-( 250 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl)-3-isopropylurea Pr, 1-((S)-fluoro((R or i /9 HN-11 F S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( / I
251 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl)-3-isopropylurea 1-isopropyl-3-((S)-2, 2,2-trifluoro-1-((R
iPr\
HN-f< pF3 or HN ' S)-3-(2-(5-fluorothio / I
252 S F phen-2-yl)ethyl)-1-( 2-(6-methylpyridin-1\1 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-isopropyl-3-((R)-2 ,2,2-trifluoro-1-((R
iFrµ 0 or HN-F_t CF3 S)-3-(2-(5-fluorothio 253 / I phen-2-yl)ethyl)-1-( N S F
2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea (R or S)-1-(2-(3-(2-(5-fluo Pr, p HN-t( CH3 rothiophen-2-yl)ethy 254 1)-1-(2-(6-methylpyr N S F idin-3-yl)propan-2-y 1)pyrrolidin-3-yl)pro pan-2-y1)-3-isopropy lurea Pr 1-(1-fluoro-1-((R or HN¨e< CH3 HN¨F S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 255 N s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -isopropylurea 1-isopropy1-3-(1,1,1 -trifluoro-2-((R or IPHr,N4 cH3 S)-3-(2-(5-fluorothio HN¨CF3 phen-2-yl)ethyl)-1-( 256 N S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-yl)urea (R or iPr, F S)-1-(difluoro(3-(2-( 5-fluorothiophen-2-S F I yl)ethyl)-1-(2-(6-me t hylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)-3-isopr opylurea (R or S)-1-(1,1,1,3,3,3-hex Pr, 0 afluoro-2-(3-(2-(5-fl HN¨Ft_pcF3 uorothiophen-2-yl)et 258 \¨ONF hyl)-1-(2-(6-methylp yridin-3-yl)propan-2 -yl)pyrrolidin-3-yl)p ropan-2-y1)-3-isopro pylurea 1-((R)-1-((R or Ph ;
HN¨ S)-3-(2-(5-fluorothio HN phen-2-yl)ethyl)-1-( 259 2-(6-methylpyridin-F 3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -phenylurea Ph 0 1-((S)-1-((R or I-1\14 S)-3-(2-(5-fluorothio HN \ -ON phen-2-yl)ethyl)-1-( 260 s F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -phenylurea Ph, 0 1-((R)-fluoro((R or HN4 F S)-3-(2-(5-fluorothio HN
/ I phen-2-yl)ethyl)-1-( 261 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl)-3-phenylurea Ph ,0 1-((S)-fluoro((R or HsN F S)-3-(2-(5-fluorothio HN
/ I phen-2-yl)ethyl)-1-( 262 S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl)-3-phenylurea 1-phenyl-3-((S)-2,2, Ph, 0 HN¨ CF3 2-trifluoro-1-((R or HN 263 S S)-3-(2-(5-fluorothio / I phen-2-yl)ethyl)-1-( F
2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea 1-phenyl-3-((R)-2,2, 2-trifluoro-1-((R or Ph 0 HN CF3 S)-3-(2-(5-fluorothio HN-phen-2-yl)ethyl)-1-( 264 NN \SF
3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)ur ea Ph 0 (R or CH&HN_13 S)-1-(2-(3-(2-(5-fluo rothiophen-2-yl)ethy 265 N s F 1)- 1-(2-(6-methylpyr =
idin-3-yl)propan-2-y N 1)pyrrolidin-3-yl)pro pan-2-y1)-3-phenylu rea Ph 0 1-(1-fluoro-1-((R or HsN1N CH
S)-3-(2-(5-fluorothio phen-2-yl)ethyl)-1-( 266 N S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)ethyl)-3 -phenylurea 1-phenyl-3-(1,1,1-tri fluoro-2-((R or Ph 0 h11\1¨ CH3 S)-3-(2-(5-fluorothio HN¨CF3 267 phen-2-yl)ethyl)-1-( S F 2-(6-methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)propan-2-yl)urea (R or Ph 0 S)-1-(difluoro(3-(2-( HsN F F
5-fluorothiophen-2-yl)ethyl)-1-(2-(6-me S F thylpyridin-3-yl)pro pan-2-yl)pyrrolidin-N 3-yl)methyl)-3-phen ylurea (R or Ph 0 S)-1-(1,1,1,3,3,3-hex HsN1N CF3u3 afluoro-2-(3-(2-(5-fl / I uorothiophen-2-yl)et 269 N S F hyl)-1-(2-(6-methylp yridin-3-yl)propan-2 -yl)pyrrolidin-3-yl)p ropan-2-y1)-3-pheny lurea 270 (R or 498 1HNMR (300 MHz, Me0D):
S)-1-(4-fluorophenyl 6 8.76 (s, 1H), 8.21 (s, 1H), )-3-((3-(2-(5-fluorot 7.47 (d, J= 8.3 Hz, 1H), 7.32 hiophen-2-yl)ethyl)- (dd, J= 8.8, 4.5 Hz, 2H), 7.21 HN1NNH 1-(2-(6-methylpyridi (t, J= 8.5 Hz, 2H), 6.47 (s, n-3-yl)propan-2-yl)p 1H), 6.35-6.27 (m, 1H), N S F
citrte yrrolidin-3-yl)methy 3.48-3.41 (m, 2H), 2.94-2.74 1)guanidine citrate (m, 7H), 2.72-2.64 (m, 2H), 2.58 (s, 3H), 2.10-1.91 (m, 2H), 1.83-1.74 (m, 9H).

F (R or 0*F S)-5-(2-(3-(ethoxydi ) fluoromethyl)-3-(24 271 s F 5-fluorothiophen-2-yl)ethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine (R or S)-4-(2-(3-(ethoxym ethyl)-1-(2-(6-methy ) 4NH
1/ 1pyridin-3-yl)propan 272 -2-yl)pyrrolidin-3-y1 )ethyl)-1H-thieno[3, ==LN.õ
4-d]imidazol-2(3H)-one (R or N
/NH S)-4-(2-(3-(ethoxym ) ethyl)-1-(2-(6-methy 273 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)-1H-thieno[3, 4-d]imidazole (R or S)-4-(2-(3-(ethoxym Nn_ ethyl)-1-(2-(6-methy 274 N) 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)-1-methy1-1H
-thieno[3,4-d]imidaz ole (R or ¨\o_\ S)-5-(2-(3-(ethoxym [,1 ethyl)-1-(2-(6-methy ) \
275 N S N 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)-1H-thieno[2, 3-d]imidazole (R or ¨\o S)-5-(2-(3-(ethoxym N ethyl)-1-(2-(6-methy / I
276 N sN 1pyridin-3-yl)propan -2-yl)pyrrolidin-3-y1 )ethyl)-1-methy1-1H
-thieno[2,3-d]imidaz ole (S)-4-((R or ,HN =
S)-3-(2-(5-fluorothio /
phen-2-yl)ethyl)-1-( \
277 s F 2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr rolidin-3-y1)-3,4-dih ydroquinazolin-2(1 H)-one (R)-4-((R or S)-3-(2-(5-fluorothio 0 I\IN phen-2-yl)ethyl)-1-( 278 S F 2-(6-methylpyridin-N 3-yl)propan-2-yl)pyr rolidin-3-y1)-3,4-dih ydroquinazolin-2(1 H)-one (R or S)-5-(2-(3-(2-(5-fluo N
rothiophen-2-yl)ethy \ 279 CT l)-3-(4-methyl-4H-1, 2,4-triazol-3-yl)pyrr olidin-l-yl)propan-2 I
-y1)-2-methylpyridin 280 (S or 493 1HNMR (300 MHz, Me0D):
R)-5-(2-(3-(5-(4-flu 6 8.62 (s, 1H), 7.99 (dd, J =
oropheny1)-1H-imid 8.4, 2.3 Hz, 1H), 7.70 (dd, J=
azol-2-y1)-3-(2-(5-fl 8.5, 5.3 Hz, 2H), 7.46-7.31 uorothiophen-2-yl)et (m, 2H), 7.14 (t, J= 8.8 Hz, F hyl)pyrrolidin-l-yl)p 2H), 6.31 (t, J= 3.6 Hz, 1H), HN iN ropan-2-y1)-2-methy 6.22 (dd, J= 3.9, 2.1 Hz, 1H), S F 1pyridine citrate 3.72 (d, J= 11.1 Hz, 1H), 3.41- 3.28 (m, 1H), 3.21 (d, J
= 10.9 Hz, 2H), 2.92-2.73 (m, 4H), 2.68-2.59 (m, 1H), 2.48 (s, 4H), 2.41- 2.27 (m, 1H), 2.22 (m, 3H), 1.74 (d, J= 5.0 Hz, 6H).

281 (S or 467 1H NMR (300 MHz, Me0D):
R)-6-fluoro-2-(3-(2- 6 8.62 (s, 1H), 8.00 (d, J= 8.0 (5-fluorothiophen-2- Hz, 1H), 7.51 (dd, J= 8.7, 4.6 F
yl)ethyl)-1-(2-(6-me Hz, 1H), 7.27 (dd, J= 22.7, HN IN thylpyridin-3-yl)pro 8.5 Hz, 2H), 7.04 (s, 1H), / pan-2-yl)pyrrolidin- 6.27 (s, 1H), 6.19 (s, 1H), N S
F 3-y1)-1H-benzoidli 3.73 (d, J= 10.0 Hz, 1H), citrate midazole citrate 3.39-3.33 (m, 1H), 3.25-3.10 (m, 2H), 2.93-2.74 (m, 6H), 2.48 (s, 3H), 2.35-2.11 (m, 4H), 1.72 (d, J= 6.7 Hz, 6H).
282 (S or 455 1H NMR (300 MHz, Me0D):
R)-5-(2-(3-(5-(tert-b 6 8.45 (s, 1H), 7.85 (d, J= 8.2 uty1)-1H-imidazol-2 Hz, 1H), 7.34 (d, J= 8.1 Hz, -y1)-3-(2-(5-fluoroth 1H), 7.06 (s, 1H), 6.30 (s, -)e\N
HN iophen-2-yl)ethyl)py 1H), 6.24 (s, 1H), 3.11 (d, J=
N
/ rrolidin-l-yl)propan- 9.3 Hz, 1H), 3.05-2.96 (m, S F
¨1 citrate 2-y1)-2-methylpyridi 2H), 2.93-2.74 (m, 4H), 1\1 ne citrate 2.65-2.43 (m, 6H), 2.36-2.25 (m, 1H), 2.22-2.11 (m, 2H), 1.99(s, 1H), 1.50 (d, J = 6.2 Hz, 6H), 1.34 (s, 9H).
5-(2-((R or S)-3-((R)-6,7-difluor oisochroman-1 -y1)-3 283 / -(2-(5-fluorothiophe S F n-2-yl)ethyl)pyrrolid in-1-yl)propan-2-y1) -2-methylpyridine F F 5-(2-((R or S)-3-((R)-6,7-difluor oisochroman-3-y1)-3 284 -(2-(5-fluorothiophe / I
n-2-yl)ethyl)pyrrolid in-1-yl)propan-2-y1) -2-methylpyridine (R or S)-5-(2-(3-(2-(5-fluo \ rothiophen-2-yl)ethy 285 N sSF 1)-3-(isobutoxymeth yl)pyrrolidin-l-yl)pr opan-2-y1)-2-methyl pyridine (S or R)-1-(4-fluoropheny 1)-34(3-(2-(5-fluorot hiophen-2-yl)ethyl)-S F 1-(2-(6-methylpyridi t n-3-yl)propan-2-yl)p yrrolidin-3-yl)methy 1)urea (S or R)-1-(4-chloropheny 1)-34(3-(2-(5-fluorot H
hiophen-2-yl)ethyl)-N 1-(2-(6-methylpyridi n-3-yl)propan-2-yl)p yrrolidin-3-yl)methy 1)urea (S or R)-1-(3,4-difluoroph eny1)-34(3-(2-(5-flu F NA orothiophen-2-yl)eth N S F y1)-1-(2-(6-methylPY
ridin-3-yl)propan-2-yl)pyrrolidin-3-yl)m ethyl)urea (S or R)-1-(5-fluoropyridi n-2-y1)-3-((3-(2-(5-fl 289 H uorothiophen-2-yl)et S F hyl)-1-(2-(6-methylp yridin-3-yl)propan-2 -yl)pyrrolidin-3-y1) methyl)urea 5-(2-((R or S)-3-(ethoxy(pyridin ¨\o -3-yl)methyl)-3-(24 290 5-fluorothiophen-2-N s F
yl)ethyl)pyrrolidin-1 -yl)butan-2-y1)-2-me N
thylpyridine CN (S or R)-5-(2-(3-(2-(5-flu / I
291 S F orothiophen-2-yl)eth y1)-3-(piperidin-1 -y1 methyl)pyrrolidin-1-yl)propan-2-y1)-2-m ethylpyridine (S or /--\
HN N R)-1-((3-(2-(5-fluor \-(x othiophen-2-yl)ethyl N s 292 F )-1-(2-(6-methylpyri N din-3-yl)propan-2-y1 )pyrrolidin-3-yl)met hyl)piperazine (S or R)-1-((3-(2-(5-fluor )¨NrA othiophen-2-yl)ethyl / I 293 N )-1-(2-(6-methylpyri S F din-3-yl)propan-2-y1 ¨i) N )pyrrolidin-3-yl)met hyl)-4-isopropylpipe razine o (R or (4N¨\ S)-1-((3-(2-(5-fluoro / ( \ thiophen-2-yl)ethyl) Ni 294 S F -1-(2-(6-methylpyrid ¨i- in-3-yl)propan-2-y1) N pyrrolidin-3-yl)meth yl)piperidin-2-one (R or /--\
ON S)-4-(2-(3-(2-(5-fluo \ (T rothiophen-2-yl)ethy N S----N
295 F 1)-1-(2-(6-methylpyr = =
Min-3-yl)propan-2-y N
1)pyrrolidin-3-yl)pro pan-2-yl)morpholine (S or /--\ R)-1-((3-(2-(5-fluor HN N
) othiophen-2-yl)ethyl N s F )-1-(2-(6-methylpyri ¨.I din-3-yl)propan-2-y1 N )pyrrolidin-3-yl)met hyl)-3,3-dimethylpip erazine ¨\o¨\ 5-(2-(3-(ethoxymeth ----)C-- I y1)-3-(2-(5-fluorothi ---/
297 N I s---NF ophen-2-y1)-2-methy ¨r 1propyl)pyrrolidin-l-N yl)propan-2-y1)-2-m ethylpyridine 5-(2-(3-(2,2-difluoro ¨\o¨\ -2-(5-fluorothiophen N)F")¨(-1 -2-yl)ethyl)-3-(ethox F S"---F
ymethyl)pyrrolidin--r 1-yl)propan-2-y1)-2-N
methylpyridine 5-(2-(3-(ethoxymeth ¨\o¨\ y1)-3-(2-(5-fluorothi 1\1) ) ei ophen-2-yl)propyl)p 299 s F
yrrolidin-l-yl)propa N n-2-y1)-2-methylpyri dine 5-(2-(3-(ethoxymeth ¨\o¨\ y1)-3-(2-fluoro-2-(5-) 0, fluorothiophen-2-y1) 300 NF s F
ethyl)pyrrolidin-l-y1 N )propan-2-y1)-2-met hylpyridine 1 5-(2-(3-(ethoxymeth 1 \ F y1)-4,4-difluoro-3-(2 F
F s -(5-fluorothiophen-2 N -yl)ethyl)pyrrolidin----) 1-yl)propan-2-y1)-2-N methylpyridine 5-(2-(3-(ethoxymeth 1 \ F y1)-3-(2-(5-fluorothi s ophen-2-yl)ethyl)-4, N 4-dimethylpyrrolidin -1-yl)propan-2-y1)-2 N -methylpyridine 5-(2-(3-(ethoxymeth o 1 \ F y1)-4-fluoro-3-(2-(5-F

s fluorothiophen-2-y1) N ethyl)pyrrolidin-l-y1 ---) )propan-2-y1)-2-met N hylpyridine 5-(2-(3-(ethoxymeth o 304 1 \ F y1)-3-(2-(5-fluorothi s ophen-2-yl)ethyl)-4-N methylpyrrolidin-1-yl)propan-2-y1)-2-m N ethylpyridine 5-(2-(4-(ethoxymeth i \ F y1)-4-(2-(5-fluorothi s 305 ophen-2-yl)ethyl)-2, N 2-dimethylpyrrolidin ----)--0õ,, -1-yl)propan-2-y1)-2 N -methylpyridine 5-(2-(4-(ethoxymeth o 1 \ F y1)-2,2-difluoro-4-(2 s 306 F -(5-fluorothiophen-2 F N -yl)ethyl)pyrrolidin----7 1-yl)propan-2-y1)-2-N methylpyridine ) 5-(2-(4-(ethoxymeth i \ F y1)-4-(2-(5-fluorothi s 307 ophen-2-yl)ethyl)-2-N methylpyrrolidin-1-yl)propan-2-y1)-2-m N ethylpyridine 5-(2-(4-(ethoxymeth 1 \ F y1)-2-fluoro-4-(2-(5-308 s fluorothiophen-2-y1) F N ethyl)pyrrolidin-l-y1 -----)-0,_ )propan-2-y1)-2-met N hylpyridine (S or R)-5-(2-(3-(2,2-diflu F
F i \ F orobuty1)-3-(2-(5-flu s 309 orothiophen-2-yl)eth N
yl)pyrrolidin-l-yl)pr N opan-2-y1)-2-methyl pyridine (R or 1 \ F S)-5-(2-(3-((1,1-difl o s uoroethoxy)methyl)-310 --N 3-(2-(5-fluorothioph +0---/ - en-2-yl)ethyl)pyrroli N
din-l-yl)propan-2-y1 )-2-methylpyridine F (R or F S)-5-(2-(3-(2-(5-fluo s 311 N rothiophen-2-yl)ethy 0¨ 1)-3-((1,1,2,2-tetraflu N oroethoxy)methyl)p yrrolidin-l-yl)propa n-2-y1)-2-methylpyri dine 5-(1-((R or I F S)-3-(ethoxymethyl) -3-(2-(5-fluorothiop 312 F hen-2-yl)ethyl)pyrro lidin-1 -y1)-1 -fluoroe thyl)-2-methylpyridi ne 313 (S or 440 1H NMR (300 MHz, Me0D):
R)-N-((3-(2-(5-fluor 6 8.67 (s, 1H), 8.06 (d, J= 8.1 othiophen-2-yl)ethyl Hz, 1H), 7.41 (d, J= 8.2 Hz, )-1-(2-(6-methylpyri 1H), 6.44 (t, J=3.6 Hz, 1H), din-3-yl)propan-2-y1 6.29 (dd, J= 3.9, 2.1 Hz, 1H), /
s F )pyrrolidin-3-yl)met 3.26-3.17 (m, 2H), 3.15-3.06 ..c.:trate hyl)methanesulfona (m, 3H), 2.94 (s, 3H), mide citrate 2.90-2.72 (m, 6H), 2.71-2.64 (m, 2H), 2.56 (s, 3H), 1.92-1.83 (m, 2H), 1.78 (s, 6H), 1.75-1.72 (m, 1H).
(S or R)-4-fluoro-N-((3-(2 -(5-fluorothiophen-2 0 µ1,1 \ -yl)ethyl)-1-(2-(6-m S ethylpyridin-3-yl)pr opan-2-yl)pyrrolidin -3-yl)methyl)benzen esulfonamide (S or R)-5-(2-(3-(2-(5-flu F3cm) 315 orothiophen-2-yl)eth / \
s F y1)-3-((2,2,2-trifluor oethoxy)methyl)pyrr olidin-l-yl)propan-2 -y1)-2-methylpyridin (S or R)-N-((3-(2-(5-fluor yoõo othiophen-2-yl)ethyl s;N
H is F )-1-(2-(6-methylpyri 316 din-3-yl)propan-2-y1 +0¨

)pyrrolidin-3-yl)met hyl)propane-2-sulfo namide (S or R)-2-(3-(2-(5-fluorot H2N / \ hiophen-2-yl)ethyl)-S

F1-(2-(6-methylpyridi n-3-yl)propan-2-yl)p yrrolidin-3-yl)propa n-2-amine (S or R)-N-(2-(3-(2-(5-flu oõo orothiophen-2-yl)eth /s \ F y1)-1-(2-(6-methylpy 318 ridin-3-yl)propan-2-0-- yl)pyrrolidin-3-yl)pr opan-2-yl)methanes ulfonamide 319 N-((R & S)-((S or 517 1H NMR (300 MHz, Me0D):
R)-3-(2-(5-fluorothi 6 8.58 (d, J= 7.5 Hz, 2H), ophen-2-yl)ethyl)-1- 7.96 (d, J= 8.4 Hz, 1H), 7.82 (2-(6-methylpyridin- (t, J= 7.9 Hz, 1H), 7.53 (d, J
\-1 ¨N 3-yl)propan-2-yl)pyr = 7.7 Hz, 1H), 7.37 (d, J=7.8 O'N'N o \¨C1 rolidin-3-y1)(pyridin Hz, 2H), 6.39 (s, 1H), 6.28 (s, N
-2-yl)methyl)methan 1H), 4.64 (s, 1H), 3.50 (m, citrate esulfonamide citrate 1H), 2.88-2.72 (m, 8H), 2.70-2.62 (m, 1H), 2.56-2.52 (m, 6H), 2.32-2.18 (m, 1H), 1.93-1.90 (m, 1H), 1.87-1.50 (m, 8H).
320 (S or 468 1H NMR (300 MHz, Me0D):
R)-N-((3-(2-(5-fluor 68.64 (s, 1H), 8.00 (d, J= 8.2 othiophen-2-yl)ethyl Hz, 1H), 7.38 (d, J= 8.1 Hz, ¨6 )-1-(2-(6-methylpyri 1H), 6.44 (s, 1H), 6.30 (d, J=
HN
din-3-yl)propan-2-y1 3.0 Hz, 1H), 3.34 (s, 3H), / I
N S F )pyrrolidin-3-yl)met 3.15-3.03 (m, 4H), 2.80 (q, J
citrate hyl)propane-2-sulfo = 15.5 Hz, 4H), 2.70-2.63 (m, namide citrate 3H), 2.55 (s, 3H), 1.85-1.75 (m, 3H), 1.72 (s, 6H), 1.33 (d, J= 6.7 Hz, 6H).
321 N-((R & S)-((S or 593 'H NMR (300 MHz, Me0D):
/ R)-3-(2-(5-fluorothi 6 8.61 (s, 1H), 8.40-8.28 (m, -0 ophen-2-yl)ethyl)-1- 1H), 8.09-7.81 (m, 1H), 7.41 C)--HN
/
(2-(6-methylpyridin- (q, J= 7.9, 7.1 Hz, 4H), I
N S F 3-yl)propan-2-yl)pyr 7.14-7.08 (m, 1H), 6.98 (dd, J
citrate rolidin-3-y1)(pyridin = 34.6, 8.0 Hz, 3H), 6.37 (s, -2-yl)methyl)-4-met 1H), 6.27 (t, J= 3.1 Hz, 1H), hylbenzenesulfonam 4.41 (s, 1H), 3.55 (m, 1H), ide citrate 3.08-2.67 (m, 1H), 2.88-2.72 (m, 8H), 2.55 (d, J= 7.2 Hz, 3H), 2.27 (m, 3H), 2.22-2.17 (m, 1H), 1.93-1.60 (m, 9H).
322 (S or 442 1H NMR (300 MHz, Me0D):
R)-((3-(2-(5-fluoroth 68.70(s, 1H), 8.11 (d, J=4.8 HR iophen-2-yflethyl)-1 Hz, 1H), 8.46 (d, J= 8.1 Hz, -(2-(6-methylpyridin 1H), 6.45 (s, 1H), 6.30 (s, HN
/ I -3-yl)propan-2-yl)py 1H), 3.60-3.54 (m, 2H), F rrolidin-3-yl)methyl) 3.11-3.03 (m, 2H), 2.88-2.81 citrate sulfamic acid citrate (m, 6H), 2.79-2.62 (m, 2H), 2.58 (s, 3H), 2.15-1.93 (m, 2H), 1.87 (s, 6H), 1.76 (d, J=
8.4 Hz, 2H).
(S or Jo( R)-N-(2-(3-(2-(5-flu orothiophen-2-yl)eth 323 s F y1)-1-(2-(6-methylpy ridin-3-yl)propan-2-N yl)pyrrolidin-3-yl)pr opan-2-yl)acetamide (S or R)-N-(2-(3-(2-(5-flu 0õ0 orothiophen-2-yl)eth 40 '11 F y1)-1-(2-(6-methylpy ridin-3-yl)propan-2-yl)pyrrolidin-3-yl)pr opan-2-yl)benzenesu lfonamide (R or NH S)-1-((3-(2-(5-fluoro H2N N thiophen-2-yl)ethyl) 325 S F -142-(6-methylpyrid in-3-yl)propan-2-y1) pyrrolidin-3-yl)meth yl)guanidine (R or S)-1-(4-fluorophenyl NNH

)-3-((3-(2-(5-fluorot h.
326 H s tophen-2-yflethyl)-1-(2-(6-methylpyridi n-3-yl)propan-2-yl)p yrrolidin-3-yl)methy 1)guanidine (R or S)-2-(3-(2-(5-fluorot oõo hiophen-2-yl)ethyl)-H2N=s;
1-(2-(6-methylpyridi s F
n-3-yl)propan-2-yl)p yrrolidin-3-yl)propa n-2-y1 sulfamoylamine (R or S)-((3-(2-(5-fluoroth Jo ,O iophen-2-yl)ethyl)-1 H

328 F -(2-(6-methylpyridin s -3-yl)propan-2-yl)py rrolidin-3-yl)methyl) sulfamoyl propan-2-yl-amine (R or S)-((3-(2-(5-fluoroth F op oxo iophen-2-yl)ethyl)-1 -(2-(6-methy1pyridin 329 s F
N -3-yl)propan-2-yl)py rrolidin-3-yl)methyl) sulfamoyl 4-fluorophenylamin (S or R)-5-(2-(3-(1-(tert-b uty1)-1H-imidazol-2 \__CT -y1)-3-(2-(5-fluoroth 330 S F iophen-2-yl)ethyl)py 2-y1)-2-methylpyridi ne (S or R)-5-(2-(3-(5-(tert-b uty1)-1H-imidazol-2 HN
-y1)-3-(2-(5-fluoroth SF / I
iophen-2-yl)ethyl)py rrolidin-l-yl)propan-N 2-y1)-2-methylpyridi ne (S or F
R)-6-fluoro-2-(3-(2-N
(5-fluorothiophen-2-HN / yflethyl)-1-(2-(6-me I thylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-y1)-1H-benzo[d]i midazole Legend for Tables I, III, V; 4th & 5th Columns: Electrospray ionization (ESI) was used in mass spectrometry for the compounds with a measured mass result shown in the fourth column. The right-most (fifth) column shows the H NMR of such compounds in Me0D at 300 MHz.
Table II: Chirality and in vivo testing of certain compounds of Table I
Compound EDso (mg/kg) Configuration at 30 mm on C57BL/6 mice in Warm-water No. Tail-flick Test 1 5 ++
2 5 ++
3 5 ++
4 5 ++
(S&R, S) ++
6 5 ++
7 5 ++
8 5 ++
9 5 ++
(S, S or R) ++
11 (S, S or R) ++
12 (S, S or R) ++
13 (S, S or R) ++
14 5 ++
5 ++
16 5 ++

18 5 ++
19 5 ++
5 ++

21 S ++
22 S ++
23 S ++
24 S ++
25 S ++
26 S ++
27 S ++
28 S ++
29 (S&R) ++
30 S ++
31 S ++
32 S ++
33 S ++
34 ( R&S, S) ++
35 (S or R, S) ++
36 S ++
37 (S or R, S) ++
38 S ++
39 S ++
40 S ++
41 S ++
42 S ++
43 S ++
44 R ++
45 R +
82 S ++
83 S ++
84 S ++
85 S ++
86 (S, R&S) ++
87 (S, S or R) ++
88 (S, S or R) ++
89 (S, S or R) ++
90 (S, R&S) ++
91 (R&S) ++
92 (R&S) ++
93 S ++

94 (S, S or R) ++
95 (S, S or R) ++
96 (S, S or R) ++
97 (S, S or R) ++
98 (S, S or R) ++
99 (R&S) ++
100 (R&S) ++
101 (R&S) ++
102 S +
103 (S, R&S) ++
104 (S, S or R) ++
105 (S, S or R) ++
106 S ++
107 S ++
108 S ++
109 S ++
110 S +
111 S ++
112 (R&S, S) ++
113 S ++
114 S ++
115 S ++
116 S ++
117 S ++
118 S ++
119 S ++
120 S ++
121 S ++
122 R ++
123 R ++
124 R +
125 S +
126 S ++
127 S ++
235 R +
270 R +
280 S ++

281 S ++
282 S ++
313 S ++
319 (R&S, S) ++
320 S ++
321 (R&S, S) ++
322 S ++
Legend for Table II, middle column:
"S" means the S enantiomer was tested with the result shown in the right-most column.
"R" means the R enantiomer was tested with the result shown in the right-most column.
"R&S" means the racemate was tested.
"S, S or R" means the compound has two chiral centers and can possibly have four diastereomers. The compound with S at the 1st chiral center and S or R at the 2nd chiral center was tested.
"R, R&S" means the compound has two chiral centers and can possibly have four diastereomers. The compound with R at the 1st chiral center and the racemate at the 2nd chiral center was tested.
"S, R&S" means the compound has two chiral centers and can possibly have four diastereomers. The compound with S at the 1st chiral center and the racemate at the 2nd chiral center was tested.
Right-most Column in Table II:
Shows results from an antinociception and warm-water tail-flick test, using male C57BL/6 mice (20-30 g; 6-12 wks), maintained on a 12-h light/dark cycle with rodent chow and water available ad libitum, and housed separately until testing.
Antinociception was assessed using the 55 C warm-water tail-flick test. The latency to the first sign of a rapid tail flick was taken as the behavioral endpoint.
Each mouse was first tested for baseline latency by immersing its tail in the water and recording the time to response. Mice not responding within 2 secs were excluded from further testing. Responsive mice were then s.c. administered the test compound and tested for antinociception at 30 min, 60 min, 90 min, and 120 min time points afterward.
Antinociception was calculated using the following formula: percentage of antinociception=100 x (test latency-control latency)/(20-control latency). To avoid tissue damage, a maximum score was assigned (100%) to animals that failed to respond within 20 secs.
Table III: New Compounds with a pyrrolidine ring and a non- pyridine-like molecule bonded to the pyrrolidine N-constituent MS
Compou Structure Name (ESI+): H-NMR
nd No.
1M+H1+
1H NMR (300 MHz, CDC13): 5 7.39 -7.28 (m, 2H), 7.03 (d, J =
8.0 Hz, 2H), 6.46 (s, 2H), 3.43-3.36 (m, 2H), (R or 3.19 (q, J= 8.8 Hz, 0 S)-3-(ethoxymeth 2H), 2.62 (t, J= 8.4 Hz, / I y1)-3-(2-(5-methy 2H), 2.49 (dd, J= 11.1, N s 1 lthiophen-2-yl)eth 386 6.9 Hz, 2H), 2.39 (d, J
40 y1)-1-(2-(p-tolyl)p = 9.0 Hz, 1H), 2.35 (s, ropan-2-yl)pyrroli 3H), 2.25 (d, J= 9.1 dine Hz, 1H), 1.78-1.67 (m, 2H), 1.47 (t, J= 6.8 Hz, 2H), 1.33 (t, J= 7.2 Hz, 3H), 1.28 (s, 6H), 1.09 (t, J= 7.2 Hz , 3H).
1H NMR (300 MHz, (S)-1-(4-bromobe Me0D): 7.53 (d, J =

E.- nzy1)-3-(ethoxym 8.1 Hz, 2H), 7.32 (d, J
2 ethyl)-3-phenethy 402 = 8.1 Hz, 2H), 1pyrrolidine 7.30-7.21 (m, 2H), 40 Br 7.19-7.10 (m, 3H), 3.86-3.77 (m, 2H), 3.51 (q, J= 7.2 Hz, 2H), 3.37 (s, 2H), 2.91-2.77 (m, 3H), 2.60-2.51 (m, 3H), 1.86-1.71 (m, 4H), 1.21 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.68-7.59 (m, 4H), 7.27-7.22 (m, 2H), 7.17-7.12 (m, 3H), (S)-1-(2-(4-bromo 3.52 (q, J= 8.4 Hz, 0 \
F phenyl)propan-2- 2H), 3.42-3.39 (m, 3H), 3 y1)-3-(ethoxymeth 430 3.25-3.14 (m, 2H), citrate y1)-3-phenethylpy 2.97-2.88 (m, 1H), Br rrolidine citrate 2.85-2.69 (m, 4H), 2.55-2.49 (m, 2H), 2.04-1.81 (m, 2H), 1.78 (s, 6H), 1.18 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.43 (d, J=
8.1 Hz, 2H), 7.33-7.25 (R)-1-(4-bromobe (m, 2H), 7.22-7.14 (m, nzy1)-3-(ethoxym ethyl)-3-phenethy 402 5H), 3.52-3.43 (m, 4H), 3.35-3.25 (m, 2H), 1pyrrolidine 2.62-2.57 (m, 5H), 2.28 1101 (d, J= 9.6 Hz, 1H), Br 1.81-1.68 (m, 2H), 1.69-1.61 (m, 2H), 1.18 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.41-7.36 (m, 4H), 7.28-7.22 (m, 2H), 7.18-7.11 (m, 3H), (R)-1-(2-(4-brom 3.48 (q, J= 6.9 Hz, ophenyl)propan-2 -y1)-3-(ethoxymet 430 2H), 3.33-3.25 (m, 2H), 2.62-2.52 (m, 4H), 2.48 hyl)-3-phenethylp (d, J= 9.0 Hz, 1H), 101 Br yrrolidine 2.31 (d, J= 9.0 Hz, 1H), 1.82-1.65 (m, 2H), 1.68-1.51 (m, 2H), 1.33 (s, 6H), 1.18 (t, J= 6.9 Hz, 3H).

1H NMR (300 MHz, Me0D): 7.34-7.31 (m, 4H), 7.25-7.21 (m, 2H), 7.16-7.12 (m, 3H), o (S)-1-(4-chlorobe 3.52 (s, 2H), 3.48 (q, J

nzy1)-3-(ethoxym 358 = 6.9 Hz, 2H), ethyl)-3-phenethy 3.33-3.30 (m, 2H), 1pyrrolidine 2.65-2.59 (m, 3H), ci 2.58-2.51 (m, 2H), 2.33-2.30 (m, 1H), 1.78-1.64 (m, 4H), 1.18 (t, J= 6.9 Hz, 3H).
7 (R or 0 S)-3-(ethoxymeth F y1)-1-(4-fluoroben =
zy1)-3-(4-fluoroph enethyl)pyrrolidin 8 (R or 376 1HNMR (300 MHz, Me0D):
S)-1-(4-chloroben 6 7.50 (s, 4H), 7.20 (t, J =
6.8 zy1)-3-(ethoxymet Hz, 2H), 6.98 (t, J = 8.6 Hz, hyl)-3-(4-fluorop 2H), 4.50-4.20 (m, 2H), N F henethyl)pyrrolidi 3.64-3.51 (m, 3H), 3.49-3.39 [101 citrate ne citrate (m, 4H), 3.21-3.08 (m, 1H), CI 2.81 (q, J= 15.6 Hz, 4H), 2.65-2.51 (m, 2H), 2.17-1.96 (m, 2H), 1.92-1.74 (m, 2H), 1.21 (t, J= 6.9 Hz, 3H).
9 (R or 348 1HNMR (300 MHz, Me0D):
S)-(1-(4-chlorobe 6 7.50 (s, 4H), 7.21 (dd, J =
nzy1)-3-(4-fluorop 8.4, 5.4 Hz, 2H), 6.98 (t, J =
HO
henethyl)pyrrolidi 8.6 Hz, 2H), 4.86-4.68 (m, n-3-yl)methanol 2H), 4.44-4.23 (m, 2H), .0 citrate citrate 3.60-3.53 (m, 2H), 2.92-2.72 CI
(m, 6H), 2.59 (t, J= 8.4 Hz, 2H), 2.13-1.99 (m, 2H), 1.87-1.72 (m, 2H).
(S or 376 1HNMR (300 MHz, R)-1-(4-chloroben Me0D): 6 7.50 (s, 4H), 7.20 F zy1)-3-(ethoxymet (dd, J= 8.3, 5.4 Hz, 2H), hyl)-3-(4-fluorop = citrate henethyl)pyrrolidi .98 (t, J= 8.6 Hz, 2H), 4.36 CI (q, J= 12.9 Hz, 2H), 3.56 ne citrate (dd, J = 7.2, 2.2 Hz, 2H), 3.45 (s, 2H), 3.35 (s, 3H), 3.14 (d, J= 11.9 Hz, 1H), 2.94-2.71 (m, 4H), 2.59 (s, 2H), 2.05 (s, 2H), 1.83 (q, J
= 8.5 Hz, 2H), 1.22 (t, J=
7.0 Hz, 3H).
1H NMR (300 MHz, Me0D): 8.43 (d, J=
4.2 Hz, 1H), 7.79-7.73 (m, 1H), 7.68-7.59 (m, (S)-2-(2-(1-(2-(4-o 4H), 7.31-7.24 (m, 2H), bromophenyl)pro 3.45 (q, J= 6.9 Hz, pan-2-y1)-3-(etho 11 431 2H), 3.40-3.32 (m, 3H), xymethyl)pyrrolid 3.19-3.13 (m, 1H), Br in-3-yl)ethyl)pyri 2.98-2.95 (m, 1H), 2.70 dine (t, J= 8.1 Hz, 2H), 2.03-1.95 (m, 1H), 1.83-1.74 (m, 10H), 1.14 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 8.43 (d, J=
4.2 Hz, 1H), 7.79-7.73 (R)-2-(2-(1-(2-(4- (m, 1H), 7.68-7.60 (m, o 4H), 7.31-7.24 (m, 2H), bromophenyl)pro 3.45 (q, J= 6.9 Hz, pan-2-y1)-3-(etho 12 431 2H), 3.36-3.32 (m, 3H), xymethyl)pyrrolid 3.19-3.13 (m, 1H), 40 in-3-yl)ethyl)pyri 2.98-2.91 (m, 1H), 2.70 Br dine (t, J= 8.1 Hz, 2H), 2.03-1.95 (m, 1H), 1.83-1.74 (m, 10H), 1.14 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.50 (d, J =
(S)-1-(2-(4-chloro 2.1 Hz, 2H), 7.28-7.20 (m, 4H), 7.13-7.10 (m, glt phenyl)propan-2-3H), 3.49 (q, J = 6.9 13 y1)-3-(ethoxymeth 386 Hz, 2H), 3.32-3.31 (m, 1101 y1)-3-phenethylpy 2H), 2.62-2.59 (m, 2H), rrolidine citrate citrate CI
2.53-2.47 (m, 3H), 2.29 (d, J= 9 Hz, 1H), 1.69-1.60 (m, 4H), 1.38 (s, 6H), 1.14 (t, J= 6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.65 (d, J =
8.7 Hz, 2H), 7.44 (d, J
= 8.7 Hz, 2H), 7.23-7.21 (m, 2H), (R)-1-(2-(4-chlor 7.15-7.13 (m, 3H), 3.49 14 * ophenyl)propan-2 (q, J= 6.9 Hz, 2H), -y1)-3-(ethoxymet 386 3.34-3.30 (m, 4H), hyl)-3-phenethylp 3.14-3.09 (m, 2H), 2.98 110 yrrolidine (d, J= 10.5 Hz, 1H), ci 2.75 (d, J= 11.1 Hz, 1H), 2.54 (t, J= 8.4 Hz, 2H), 1.90-1.74 (m, 2H), 1.68 (s, 6H), 1.17 (t, J=
6.9 Hz, 3H).
1H NMR (300 MHz, Me0D): 7.72-7.68 (m, 1H), 7.68-7.58 (m, 1H), 7.49-7.47 (m, 2H), (S or 7.27-7.16 (m, 5H), R)-1-(2-(2-chloro 4.01-3.96 (m, 2H), 3.80 phenyl)propan-2- (m, 1H), 3.45-3.34 (m,
15 N y1)-3-phenethy1-3 398 3H), 3.08-3.04 (m, 1H), 1101 -((S&R)-tetrahydr 2.80 (q, J= 15.3 Hz, ofuran-2-yl)pyrrol 4H), 2.69-2.63 (m, 2H), idine 2.28 (t, J= 8.4 Hz, 2H), 2.02 (m, 3H), 2.00(d, J
= 8.7 Hz, 6H), 1.96-1.83 (m, 2H), 1.76-1.51 (m, 1H).
1H NMR (300 MHz, Me0D): 7.98 (s, 1H), 7.93 (s, 1H), 7.25-7.03 4-(2-((S or (m, 5H), 3.93-3.85 (m, R)-3-phenethy1-3-2H), 3.59-3.49 (m, 3H), ((S&R)-tetrahydr 3.16-3.10 (m, 2H), 2.80
16 ofuran-2-yl)pyrrol 354 idin-1-yl)propan-(q, J= 15.3 Hz, 4H), citrate 2.75 (m, 1H), 2.63-2.60 2-y1)-1H-pyrazole (m, 1H), 2.16-0.98 (m, citrate 5H), 1.70 (s, 6H), 1.60 (m, 1H), 1.54-1.29 (m, 2H).

______________________________________________ 1H NMR (300 MHz, Me0D): 7.84-7.61 (S or (m, 5H), 7.30-7.00 (m, 5H), 6.89 (d, J= 3.3 Hz, R)-1-(2-(4-(furan-1H), 6.56 (d, J = 4.5 0 Hz, 1H), 4.93 (br s, 2-yl)phenyl)propa
17 n-2-y1)-3-pheneth 431 0 ' I y1-3-((S&R)-tetra 1H), 3.45-3.31 (m, 2H), 2.80 (q, J= 15.3 Hz, hydrofuran-2-yl)p 4H), 2.68-2.45 (m, 2H), yrrolidine 2.30-1.95 (m, 4H), 1.88 (s, 6H), 1.86-1.60 (m, 4H), 1.39-1.29 (m, 4H).
1H NMR (300 MHz, Me0D): 7.62 (s, 1H), or 7.61-7.47 (m, 5H), R)-3-phenethy1-3- 7.28-7.14 (m, 5H), 6.60 ((S&R)-tetrahydr (d, J= 5.1 Hz, 1H),
18 ofuran-2-yl)pyrrol 431 3.88-3.70 (m, 3H), I IV IN
citrate idin-l-yl)propan- 2.90-2.70 (m, 8H), 2-y1)-1-phenyl-1 2.58-2.53 (t, J= 9.0 Hz, H-pyrazole citrate 2H), 1.93-1.84 (m, 4H), 1.71-1.57 (m, 3H), 1.49-1.46 (m, 7H).
1H NMR (300 MHz, Me0D): 7.87 (d, J =
6.3 Hz, 1H), 7.27-7.12 2-methyl-5-(2-((S (m, 5H), 3.89-3.81 (m, or 1H), 3.49-3.41 (m, 2H),
19 R)-3-phenethy1-3- 3.40 (m, 3H), 3.30 (s, 385 ((S&R)-tetrahydr 1H), 3.32-3.10 (m, 1H), ofuran-2-yl)pyrrol 2.80 (q, J= 15.3 Hz, citrate - I idin-l-yl)propan- 4H), 3.71 (s, 3H), 2-yl)thiazole 3.61-3.50 (m, 2H), citrate 2.20-2.01 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.80 (m, 6H), 1.78-1.73 (m, 3H).
1-methyl-5-(2-((S 1H NMR (300 MHz, çJTor Me0D): 7.38 (s, 1H), j R)-3-phenethy1-3- 7.28-7.23 (m, 2H),
20 ((S&R)-tetrahydr 368 7.17-7.15 (m, 3H), 6.31 C1N ofuran-2-yl)pyrrol (m, 1H), 4.11 (s, 3H), citrate idin-l-yl)propan- 3.93-3.79 (m, 1H), 2-y1)-1H-pyrazole 3.76-3.70 (m, 2H), citrate 2.91-2.75 (m, 4H), 2.71-2.58 (m, 6H), 2.00-1.75 (m, 8H), 1.63-1.62 (m, 6H).
1H NMR (300 MHz, Me0D): 5 7.61 (s, 1H), 7.29-7.24 (m, 2H), 2-methyl-4-(2-((S
7.19-7.14 (m, 3H), or 4.04-3.81 (m, m, 2H), R)-3-phenethy1-3-3.66-3.39 (m, 3H), 3.26 ((S&R)-tetrahydr
21 385 (s, 3H), 3.03 (m, 1H), ofuran-2-yl)pyrrol 2.43 (q, J= 15.6 Hz, citrate 1\2\¨A¨IN-''IVS idin-1-yl)propan-4H), 2.72-2.66 (m, 5H), 2-yl)thiazole 2.24-2.16 (m, 2H), citrate 2.14-2.00 (m, 2H), 1.80 (s, 6H), 1.62-1.53 (m, 2H).
1H NMR (300 MHz, Me0D): 7.61 (d, J =
5.1 Hz, 1H), 7.19 (dd, J
2-methyl-4-(2-((S
= 2.4, 1.2 Hz, 1H), 6.90 or (dd, J= 3.6, 1.5 Hz, \ R)-34(S&R)-tetra 1H), 6.82 (s, 1H), s hydrofuran-2-y1)-
22 391 3.93-3.90 (m, 2H), N N..1/ 3-(2-(thiophen-2-3.88-3.65 (m, 1H), citrate yl)ethyl)pyrrolidi 3.56-3.44 (m, 3H), n-1-yl)propan-2-y 2.92-2.80 (m, 7H), 1)thiazole citrate 2.77-2.68 (m, 3H), 2.11-1.95 (m, 6H), 1.80-1.73 (m, 8H).
1H NMR (300 MHz, Me0D): 5 7.81-7.76 (m, 1H), 7.17 (d, J =
2-methyl-5-(2-((S 4.8 Hz, 1H), 6.89(s, or 1H), 6.80 (s, 1H), \ R)-34(S&R)-tetra 3.89-3.81 (m, 1H), s 23 hydrofuran-2-y1)- 391 3.70-3.57 (m, 2H), N 3-(2-(thiophen-2- 3.22-3.19 (m, 2H), citrate yl)ethyl)pyrrolidi 3.09-3.05 (m, 1H), n-1-yl)propan-2-y 2.87-2.77 (m, 6H), 1)thiazole citrate 2.71-2.68 (m, 3H), 2.03-1.87 (m, 6H), 1.82-1.73 (m, 8H), 1.72-1.56 (m, 1H).

1H NMR (300 MHz, Me0D): 7.79-7.78 (m, 1H), 7.61-7.59 (m, 1H), 7.40-7.39 (m, 1H), 7.17 (d, J= 5.1 Hz, (S or 1H), 6.90-6.87 (m, 1H), R)-34(S&R)-tetra 6.80-6.78 (m, 1H), \ hydrofuran-2-y1)-3.89-3.84 (m, 2H), S 3-(2-(thiophen-2-24 376 3.78-3.55 (m, 2H), yl)ethyl)-1-(2-(thi 3.78-3.55 (m, 1H), citrate ' ophen-3-yl)propa 3.42-3.31 (m, 3H), n-2-yl)pyrrolidine 3.24-3.06 (m, 1H), 2.78 citrate (q, J= 15.3 Hz, 4H), 2.23-1.93 (m, 1H), 1.95-1.90 (m, 4H), 1.84 (s, 6H), 1.80-1.61 (m, 2H), 1.55-1.31 (m, 1H).
1H NMR (300 MHz, Me0D): 7.84-7.81 (m, 2H), 7.76-7.70 (m, 2H), 7.61 (s, 1H), 7.11-7.01 (m, 1H), 6.89 (S or (d, J= 3.3 Hz, 1H), R)-1-(2-(4-(furan-6.81-6.80 (m, 2H), 2-yl)phenyl)propa 0 6.56-6.55 (m, 1H), n-2-y1)-3-((S&R)-25 0 436 3.90-3.72 (m, 2H), citrate \ I tetrahydrofuran-2 3.69-3.65 (m, 1H), -y1)-3-(2-(thiophe 3.55-3.36 (m, 2H), n-2-yl)ethyl)pyrro 3.26-3.00 (m, 2H), lidine citrate 2.91-2.75 (m, 6H), 2.25-2.02 (m, 2H), 1.99-1.89 (m, 2H), 1.87 (s, 6H), 1.82-1.75 (m, 4H).
1H NMR (300 MHz, 1-methyl-4-(2-((S
Me0D): 7.97 (s, 1H), or 7.74 (s, 1H), 7.19 (s, R)-34(S&R)-tetra 1H), 6.91 (s, 1H), I s\ hydrofuran-2-y1)-o 6.91-6.75 (m, 1H), 26 3-(2-(thiophen-2- 374 rj 3.99-3.88 (m, 5H), citrate \ N yl)ethyl)pyrrolidi 3.75-3.35 (m, 5H), n-1-yl)propan-2-y 3.12-3.03 (m, 1H), 2.84 1)-1H-pyrazole (q, J= 15.3 Hz, 4H), citrate 2.73-2.66 (m, 1H), 2.22-2.16 (m, 6H), 1.96 (s, 6H), 1.77-1.30 (m, 2H).
(S or 1H NMR (300 MHz, Me0D): 7.80-7.69 R)-34(S&R)-tetra (m, 4H), 7.49-7.44 (m, I hydrofuran-2-y1)-0 2H), 7.13-7.08 (m, 2H), 3-(2-(thiophen-2-27 452 6.85-6.74 (m, 2H), citrate \ yl)ethyl)-1-(2-(4-( 4.88-3.37 (m, 5H), thiophen-2-yl)phe 3.25-2.91 (m, 2H), nyl)propan-2-yl)p 2.86-2.74 (m, 6H), yrrolidine citrate 2.17-1.73 (m, 14H).
1H NMR (300 MHz, Me0D): 7.17 (d, J=
2,4-dimethy1-5-(2 4.8 Hz, 1H), 6.90 (hr s, -((S 1H), 6.81 (hr s, 1H), I \ or 3.90-3.86 (m, 2H), s R)-34(S&R)-tetra 3.75-3.70 (m, 2H), 28 N S hydrofuran-2-y1)- 405 3.20-2.95 (m, 3H), N 3-(2-(thiophen-2- 2.94-2.86 (m, 4H), citrate--"\1_,\ ¨11V
yl)ethyl)pyrrolidi 2.85-2.70 (m, 4H), n-1-yl)propan-2-y 2.60-2.58 (m, 3H), 1)thiazole citrate 2.53-2.51 (m, 3H), 1.93-1.79 (m, 6H), 1.72-1.68 (m, 6H).
1H NMR (300 MHz, Me0D): 7.40 (s, 1H), 7.32 (d, J= 8.1 Hz, 1H), 7.28-7.23 (m, 2H), (R or 7.20-7.13 (m, 4H), S)-6-43-(ethoxy 4.44-4.31 (q, J= 12.9 methyl)-3-phenet Hz, 2H), 3.54 (q, J=
29 hylpyrrolidin-l-yl 381 7.2 Hz, 2H), 3.45-3.31 =oi\iso )methyl)benzo1d1 (m, 5H), 3.12 (m, 1H), oxazol-2(3H)-one 2.78 (q, J= 15.6 Hz, citrate citrate 4H), 2.60-2.57 (m, 2H), 2.10-1.99 (m, 2H), 1.89-1.80 (m, 2H), 1.21 (t, J= 7.2 Hz, 3H).
30 (R or F S)-3-(ethoxymeth y1)-3-(4-fluorophe 0S nethyl)-1-(2-(fura \!
n-2-yl)benzyl)pyr rolidine 31 (R or 0 S)-3-(ethoxymeth F y1)-3-(4-fluorophe s 40 nethyl)-1-(2-(thio phen-2-yl)benzyl) pyrrolidine 32 (R or S)-1-(2,4-dichloro F benzy1)-3-(ethoxy 40 methyl)-3-(4-fluo ci a rophenethyl)pyrro lidine 33 (R or S)-1-(2,6-dichloro F -4-fluorobenzy1)-N CI
40 3-(ethoxymethyl)-CI F 3-(4-fluorophenet hyl)pyrrolidine 34 (3R or S)-1-(chroman-4-F
y1)-3-(ethoxymeth y1)-3-(4-fluorophe nethyl)pyrrolidine 35 (3R or S)-3-(ethoxymeth N F y1)-1-(6-fluorochr F
oman-4-y1)-3-(4-f 0 luorophenethyl)p yrrolidine 36 (R or S)-3-43-(ethoxy methyl)-3-(4-fluo rophenethyl)pyrro lidin-l-yl)methyl) N
-1H-pyrazolo[4,3-cflpyrimidine 37 4-((R or F S)-3-(ethoxymeth y1)-3-(4-fluorophe nethyl)pyrrolidin-1-y1)-3,3-dimethy HN
1-3,4-dihydroisoq uinolin-1(2H)-one 38 (R or S)-3-43-(ethoxy methyl)-3-(4-fluo rophenethyl)pyrro G
N,N
lidin-l-yl)methyl) N
pyridazine-4-carb onitrile 39 (R or S)-3-43-(ethoxy methyl)-3-(4-fluo rophenethyl)pyrro lidin-l-yl)methyl) -4-(trifluoromethy 1)pyridazine 40 (R or S)-4-(2-(1-(bis(2-0 methylthiazol-4-y N CN 1)methyl)-3-(etho xymethyl)pyrrolid in-3-yl)ethyl)benz onitrile (3R or S S)-1-(1,1,1,3,3,3-0 hexafluoro-2-(p-t olyl)propan-2-y1)-3-(tetrahydrofura F30 n-2-y1)-3-(2-(thio F30 phen-2-yl)ethyl)p yrrolidine *Legend for 4th & 5th columns in Table III is same as for Table I.
Table IV: Chirality and in vivo testing of compound Nos. 1 to 25 of Table III
ED5o (mg/kg) at 30 mm on C57BL/6 Compoun Configuration mice in Warm-water tested Tail-flick Test (same as Table II) ++

3 S ++

R ++

7 S ++

11 5 ++
12 5 ++
13 5 ++
14 5 ++
(S, S&R) 16 (S, S&R) ++
17 (S, S&R) ++
18 (S, S&R) 19 (S, S&R) ++
21 (S, S&R) ++
22 (S, S&R) ++
23 (S, S&R) ++
24 (S, S&R) ++
24 (S, S&R) ++
(S, S&R) ++
26 (S, S&R) ++
27 (S, S&R) 28 (S, S&R) Legend for Table IV, middle column "S, S&R" means the compound has two chiral centers and can possibly have four diastereomers. The compound with S at the 1st chiral center and the racemate at the 2nd chiral center was tested.
Table V: New Compounds with a pyridine ring and other groups bonded to the pyridine N-constituent MS
Compound Structure Name (ESI+): H-NMR
[M+H]+

NMR (300 MHz, Me0D): 6 8.56 (d, J = 4.2 Hz, 11-1), 8.31 (d, J= 1.5 Hz, 1H), 7.80 (td, = 7.5, 1.5 Hz, 1H), 7.69 (dd, 54(4-(4-fluorophene = 8.1, 2.0 Hz, 1H), 7.49 (d, =
thyl)-4-(pyridin-2-yi 390 1 )piperi 8.1 Hz, 1H), 7.39-7.21 (m, 2H), .di n- 1 -yi)trieth y1)-2-methylpyridine 7.02-6.82 (m, 414), 3.45 (s, 211), 2.75-2.68 (m, 2H), 2.50 (s, 3H), 2.47-2.43 (m, 211), 2.19-2.14 (m, 4H), 1.93-1.85 (m, 4H).
II-1 NMR (300 MHz, Me0D): 6 8.55 (d, J = 3.6 Hz, 11-1), 8.30 (d, J= 1.8 Hz, 1H), 7.72-7.65 =F
4-fluoro-N-((14(6-in (tn., 2H), 7.48 (dõi = 7.8 Hz, " ethylpyridirt-3-yDate 1H), 7.24-7.18 (m, 211), 6.70 (t, 9 thyl)-4-(pyridin-2-y1 = 8.7, Hz, 2H), 6.40-6.30 (m, )piperidin-4-yl)meth 2H), 3.43 (s, 2H), 3.29 (s, 2H), yeaniline 2.72-2.66 (m, 2H), 2.49-2.47 (m, 5H), 1.88 (tõf = 8.4 Hz, 2H), 1.98-1.94 (m, 2H).
II-1 NMR (300 MHz, Me0D): 6 8.55 (ddõi = 4.5, 0.9 Hz, 1I-I), 8.27 (d, J= 1.8 Hz, 1H), abh F 4-fluoro-N-metItyl-7.65-7.60 (tn., 21-1), 7.40 (d, J=
N-((1-((6-methylpyri 8.1 Hz, 1H), 7.24-7.18 (m, 2H), din-3-yemethyl)-4-( 405 3 6.73-6.67 (m, 2H), 6.4-6.35 (m, n-4-ylpinethyl)aniiin 2H), 3.42 (s, 2H), 3.34 (s, 211), 2.73 (d, = 8.7 Hz, 2H), 2.62 (s, 3H), 2.60-2.56 (m, 2H), 2.48 (s, 311), 2.02-1.87 (m, 4H).
II-1 NMR (300 MHz, Me0D): 6 F 5((44(4-fluorophen 8.52 (s, -1H), 8.32 (s, 1H), N 0 "PP oxy)methyl)-4-(pyri.
392 7.80-7.75 (m, 1H), 7.69 (d, .1=
4 N din-2-yl)piperidin-l-8.1 HZ, 1H), 7.56 (d, J= 8.1 yl)rnethyl)-2-rnethyl pyridine Hz, 1H), 7.28-7.21 (m, 2H), 6.93-6.86 (m, 2I1), 6.75-6.72 (m, 2H), 4.00 (s, 2H), 3.45 (s, 211), 2.72-2.68 (m, 2H), 2.57-2.46 (m, 5H), 2.28-2.20 (m, 2H), 2.18-2.03 (m, 2H).
114 NMR (300 MHz, Me0D): 6 8.26 (s, 1H), 8.01 (d, J= 8.4 Hz, 2H), 7.78 (dõ/ = 8.4 Hz, 1-(2-(4-(2H-1,2,3-tri 2H), 7.24-7.20 (m, 2H), azol-4-y11phenyl)pro 7.15-7.12 (m, 3H), 3.48-3.42 pan-2-y1)-4-(ethoxy (m, 4H), 3.28-3.22 (m, 2H), methyl)-4-phenethyl 2.54-2.48 (m, 2H), 1.90 (s, 6H), piperidine 1.84-1.70 (m, 4H), 1.67-1.55 (m, 2H), 1.35-1.28 (m, 2H), 1.19-1.17 (m, 3H).
NMR (300 MHz, Me0D): 6 8.70 (s, 1H), 8.05-8.03 (m, 1H), 7.45 (d, J = 8.1 Hz, 11-1), 7.16 s 5-(2-(4-(ethoxymeth (d, J= 5.1 Hz, 1H), 6.90-6.87 y1)-4-(2-(thiophen-2- (m, 1H), 6.80-6.79 (m, 1H), 6 N yeethypp 387iperidin-1- 3.52-3.41 (m, 4H), 3.24-3.13 yl)propan.-2-y1)-2-m (m, 4H), 2.90-2.72 (m, 6H), ethylpyridine citrate citrate 2.58 (s, 3H), 1.97-1.86 (m, 2H), 1.85 (s, 6H), 1.77-1.70 (m, 4H), 1.23 (tõi = 7.2 Hz, 3H).
NMR (300 MHz, Me0D): 6 8.21 (s, 1H), 7.25 (s, 1H), 7.14 (dd, J =5.1, 1.2 Hz, 11-1), 6.88 (dd, J =5.1, 2.4 Hz, 1H), 3-(1-(4-(ethoxyrneth I \ 6.81-6.80 (m, 1H), 3.79 (br S.
S y1)-4-(2-(thiophen-2-7 N yl)ethyppiperidin-1-387 211), 3.53 (qõI = 6.9 Hz, 2H), I yeethyl)-2,6-dimeth 3.38 (s, 2H), 3.29-3.26 (m, 5H), ylpyridine 2.85-2.79 (m, 2H), 2.51 (s, 3H), 2.31 (s, 3H), 1.85-1.80 (En, 2H), 1.70-1.43 (m., 511), 1.17 (t, =
6.9 Hz, 3H).

'1-1NMR (300 MHz, Me0D): 6 7.27-7.12 (m, 8H), 4.30 (s, 2H), 5((4-(ethoxymethyl 3.54 (q, = 7.2 Hz, 2H), )-4-phenethylpiperid 3.32-3.30 (m, 5H), 3.21 (rn, in-l-yl)inethyl)- 1 -in 407 ethy1-1,3-dihydro-2 4H), 2.79 (qõI = 15.6 Hz, N

H-benzoldlimidazol- 4H), 2.61-2.53 (m, 2H), citrate \
2-one citrate 1.90-1.71 (m, 6H), 1.18 (t, J=
7.2 Hz, 3H).
II-1 NMR (300 MHz, D20): 6 7.32-7.24 (in, 4H), 7.22-7.18 6((4-(ethoxyrnethyl (m, 4H), 4.26-4.25 (in, 2H), )-4-phenethylpiperid 406 3.50-3.44 (m, 3H), 3.35 (s, 3M), 9 N in-1-yemethyl)-3-m 3.32-3.28 (m, 3H), 3.06-2.98 0 ethylbenzoldloxazol (ill., 2H), 2.51-2.47 (m, 2H), HCI -2(3H)-one 1-1(.71 1.89-1.51 (m, 6H), 1.08 (t, J=
7.2 Hz, 3H).
.NMR (300 MHz, Me013):
7.78 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.49 (d, .1= 8.4 Hz, 1H), 7.27-7.12 (m, 5H), 4.42 (s, 6((4-(ethoxymethyl 2H), 3.54 (ci, J= 7.2 Hz, 2H), o )-4-phenethylpiperid N in-] -ypinethyl)-2-in 392 3.47-3.45 (m, 2H), 3.22 (in, 'c)_ ethylbenzoldloxazol 4H), 2.79 (q, J = 15.3 Hz, 4H), citrate e citrate 2.66 (s, 3H), 2.59-2.54 (m, 21-1), 1.91-1.86 (m, 2H), 1.77-1.72 (m, 4H), 1.18 (t, J= 7.2 Hz, 3H).
II-1 NMR (300 MHz, Me0D): 6 7.68 (s, 1H), 7.57 (d, J= 8.1 6((4-(ethoxyrnethyl Hz, "IH), 7.32 (d, .1= 8.4 Hz, )-4-phenethylpiperid 1H), 7.27-7.12 (m, 5H), 4.40 (s, 11 2H), 3.54 (q, J = 7.2 Hz, 2H), 1\1_ ethy1-11-1-benzo[d]i 3.40 (s, 2H), 3.26 (m, 4H), 2.78 citrate rnidazole citrate ((i, J = 15.6 Hz, 41-1), 2.60 (s, 3H), 2.58-2.54 (m, 2H), 1.86-1.75 (m, 6H), 1.17 (t, J=

7.2 Hz, 3H).
'H NMR (300 MHz, Me0D): 6 7.28-7.15 (m, 5H), 6.93-6.90 (m, 2H), 6.81 (d, J = 7.8 Hz, 1((2,2-dimethylben 1H), 4.18 (s, 2H), 3.54 (qõi =
zo[rl][11,3]dioxol-5-y 12 N 1)methyl)-4-(ethoxy 409 7.2 Hz, 2H), 3.40 (m, 2H), 3.22 O methyl)-4-phenethyl (m, 4H), 2.78 (q, J = 15.6 Hz, citrate piperidine citrate 4H), 2.60-2.54 (m, 2H), 1.87-1.71 (m, 6H), 1.66 (s, 611), 1.18 (t, J= 7.2 Hz, 3H).
NMR (300 MHz, Me0D): 6 7.37-7.30 (m, 5H), 7.28-7.22 6-((4-((benzyloxy)m (m, 4H), 7.17-7.12 (m, 4H), = 0 ethyl)-4-phenethytpi 459 4.52 (s, 211), 4.27 (s, 211), 3.54 13 N peridin-l.-yl)methyl) (s, 211), 3.17 (m, 4H), 2.78 (q, N,D benzolirlioxazol-2(3 = 15.6 Hz, 4H), 2.55-2.49 (m, Citrate H
H)-one citrate 2H), 1.91-1.86 (m, 211), 1.82-1.71 (m, 4H).
11-1 NMR (300 MHz, Me0D): 6 7.33 (d, J= 8.7 Hz, 1H), 7.28-7.09 (m, 5H), 7.05 (s, 1H), 6.87 (d, J= 8.7 Hz, 1H), 4.33 2-chloro-5-(14-(etho (s, 2H), 3.54 (q, J = 7.2 Hz, xymethyt)-4-pheneth 388 OH ylpiperidin-l=-yernet 211), 3.42 (s, 2H), 3.34-3.29 (rn, ith hyl)phenol citrate 4H), 2.78 (qõI = 15.6 Hz, 4H), ci citrate 2.60-2.54 (m, 2H), 1.91-1.87 (m, 2H), 1.78-1.68 (m, 41-1), 1.29 it, J= 7.2 Hz, 3H).
NMR (300 MHz, Me0D):
7.32-7.23 (m., 311), 7.20-7.14 4-chloro-3-((4-(etho (m, 2H), 7.12-7.10 (m, 2H), xymethyl)-4-pheneth 388 7.04 (d, J = 8.1 Hz, 11-1), 4.44 OH ylpiperidin-1-yemet (s, 2H), 3.54 (q, J = 7.2 Hz, hyephenol citrate Ci 211), 3.42 (s, 2H), 3.34 (m, 4H), citrate 2.78 (qõI = 15.6 Hz, 4H), 2.60-2.54 (m, 2H), 1.93-1.88 (m, 2H), 1.79-1.69 (m, 4H), 1.21 (t, J= 7.2 Hz, 3H).
'1-1NMR (300 MHz, Me0D):
7.40-7.19 (m, 4H), 7.15-7.10 (m, 2H), 7.05 (dõi = 7.8 Hz, 6-(2-(4-(ethioxyrneth 2H) 3.67-3.34 (q, J = 7.2 Hz, ye-4-phenethylpiper 211), 3.31-3.30 (m, 4H), 16 idin-1-yl)ethyp 409benz 3.18-3.00 (m, 4H), 3.11-3.00 o[d]oxazol-2(3H)-on (m, 2H), 2.78 (q, J= 15.6 Hz, 0 e citrate 4H), 2.61-2.56 (In, 2H), citrate 1.92-1.55 (m, 6H), 1.22(t, J=
6.9 Hz, 3H).
11-1 NMR (300 MHz, Me0D):
8.02 (s, 1H), 7.90 (d, J= 7.2 Hz, 1H), 7.73 (d, ./ = 7.2 Hz, 1H), 7.29-7.12 (m, 5H), 5.43 (s, 6((4-(ethoxymethyl.
2H), 4.37 (s, 2H), 3.54 (ch J =
)-4-phenethylpiperid 17 N 0 in-1-yl)methypisobe 394 7.2 Hz, 2H), 3.40 (s, 2H), 3.18 nzafaran-1(3H)-one (m, 4H), 2.78 (q, = 15.6 Hz, citrate 4H), 2.59-2.54 (in, 2H), citrate 1.89-1.84 (m, 2H), 1.75-1.69 (m, 411), 1.29 (t, J = 6.9 Hz, 3H).
II-1 NMR (300 MHz, Me0D):
7.26-7.20 (m, 4H), 7.16-7.10 (m, 3H), 7.04 (d, J= 7.8 Hz, /0 1H), 3.54 (q, J = 7.2 Hz, 2H), 6-(2-(4-(1-ethoxycyc 3.44 (m, 2H), 3.31-3.21 (m, lo-propy1)-4-pheneth 18 ylpipericiin-1-yeethy 435 2H), 3.23-3.08 (m, 4H), 1)benzo[d]oxazol-2( 2.86-2.71 (m, 6H), 2.05-2.00 0 3H)-one citrate (m, 2H), 1.87 (d, J= 14.4 Hz, HN-citrate 0 2H), 1.671.59 (na, 2H), 1.14 (t, J = 6.9 Hz, 3H), 0.89 (ni, 2H), 0.74 (rn, 21-1).

'FINMR (300 MHz, Me0D): 6 7.49 (s, 11-1), 7.28-7.23 (m, 3H), 7.20-7.12 (m, 3H), 6.98 (d, J=
2-chloro-4((4-(etho 8.4 Hz, 1H), 4.18 (s, 2H), 3.54 xyrnethyl)-4-pheneth 19 388 (qõ,1 = 7.2 Hz, 2H), 3.39 (m, Ci ylpiperidin-1-yl)met 2H), 3.20 (m, 4H), 2.78 (q, J=
hyl)phenol citrate OH 15.6 Hz, 4H), 2.64-2.53 OM
citrate 2H), 1.85-1.71 (m, 6H), 1.19 (t, J = 7.2 Hz, 31H), II-1 NMR (300 MHz, Me0D): 6 7.49 (t, J= 7.6 Hz, 1H), 3((4-(ethoxymethyl 7.34-7.12 (m, 8H),4.28 (s, 21-1), )-4-phenethylpiperid 3.54 (q, J = 7.2 Hz, 2H), 3.40 20 N in-1-yl)methyl)phen 410 (s, 2H), 3.23 (br s, 4H), 0N' yl methylcarbamate 2.80-2.71 (m, 7H), 2.60- 2.54 citrate citrate (m, 2H), 1.86-1.75 (m, 6H), 1.20 (t, J = 6.9 Hz, 3H).
'I-1 NMR (300 MHz, Me0D): 6 7.40 (d, J= 8.1 Hz, 1H), 7.34 (s, 1H), 7.28-7.12 (m, 5H), 6.96 6((4-(ethoxyirnethyl (d, J = 7.8 Hz, 1H), 5.35 (s, )-4-phenethylpiperid 2H), 4.22 (s, 2H), 3.54 (q, J =
in--1-yl)methyi)-1,4- 408 dihyclro-2H-benzolicl 7.2 Hz, 2H), 3.39 (br s, 2H), NO ][1,3]oxazin-2-one 3.20 (br s, 4H), 2.78 (q, J=
citrate H
citrtate 15.6 Hz, 4H), 2.59-2.54 (m, 2H), 1.90-1.59 (m, 6H), 1.20 (t, = 6.9 Hz, 3H).
II-1 NMR (300 MHz, Me0D): 6 7.28-7.07 (m, 7H), 6.97 (d, J=
8.1 Hz, 1H), 4.61 (s, 2H), 4.19 7-((4-(ethoxymethyl (s, 2H), 3.54 (q, J= 7.2 Hz, )-4-phenethylpiperid 22 N in-] -ypinethyl)-2H-408 2H), 3.40 (br s, 2H), 3.20 (br s, o benzo[b][1,4]oxiizin 4H), 2.78 (q, J = 15.6 Hz, 4H), citrate H -3(4H)-one citrate 2.59-2.54 (m, 21-1), 1.85-1.62 (m, 6H), 1.19 (t, J= 7.2 Hz, 3H).

'FINMR (300 MHz, Me0D): 6 7.31-7.23 (m, 311), 7.20-7.12 (m, 3H), 6.94 (d, J = 6.6 Hz, 1.((2,3-dihydrohenz 1H), 6.87 (s, 1H), 4.58 (t, J =
ofuran-6-ypinethyp- 8.7 Hz, 214), 4.20 (s, 2H), 3.54 23 N 4-(ethoxymethyl)-4- (qõI = 7.2 Hz, 2H), 3.34 (br s, 0 phenethylpiperidine 2H), 3.29-3.20 (m, 614), 2.78 citrate citrate (q, J = 15.6 Hz, 4H), 2.59-2.54 (ti, 2H), 1.86-1.74 (m, 611), 1.19 (t, J= 6.9 Hz, 3H).
IHNMR (300 MHz, Me0D): d 7.56 (d, J = 8.1 Hz, 214), 7.41 (d, J= 8.1 Hz, 2H), 7.28-7.12 methyl (m, 5H), 4.23 (s, 2H), 3.74 (s, (4-((4-(ethoxymethy 410 311), 3.57 (qõ/ = 7.2 Hz, 214), 24 N 1)-4-phenethylpiperi 3.39 (br s, 2H), 3.22 (hr s, 4H), Nic) din-1-yl)methyl)phe 2.78 (q, J = 15.6 Hz, 4H), citrate H nyl)carbarnate citrate 2.59-2.54 (m, 2H), 1.86-1.74 (ti, 6H), 1.19 (t, J= 6.9 Hz, 3H).
1HNMR (300 MHz, Me0D): 6 7.39-7.23 (m, 511), 7.22-7.12 5((4-(ethoxymethyl. (m, 3H), 4.19 (s, 2H), 3.54 (q, J
)-4-phenethylpiperid = 7.2 Hz, 214), 3.47 (br s, 2H),
25 N in-] -ypinethyl)benz 3.21 (br s, 414), 2.78 (q, J =
N o[d]oxazol-2(3H)-on 15.6 Hz, 4H), 2.59-2.54 (n, citrate e citrate 2H), 1.85-1.75 (m, 6H), 1.19 (t, = 6.9 Hz, 3H).
it1 NMR (300 MHz, IVIe0D):
7.35-7.29 (in, 2H), 7.25-7.12 5-((4-(ethoxymethyt (m, 6H), 4.32 (s, 214), 3.54 (q, J
)-4-phenethylpiperid = 7.2 Hz, 2H), 143-3.20 (m,
26 N I in-1-ye 408 methyl)-3-m 5H), 3.22 (br s, 4H), 2.78 (q, J
N
o ethylhenzo[d]oxazol = 15.6 Hz, 4H), 2.60-2.54 (m, citrate -2(31:1)-one citrate 2H), 1.91-1.65 (m, 6H), 1.19 4, J = 6.9 Hz, 311).

'FINMR (300 MHz, Me0D): 6 7.52 (d, i = 8.4 Hz, 11-1), 7.39 6-((4-(ethoxymethyl (s, 1H), 7.28-7.12 (m, 6H), 5.28 )-4-phenethylpiperid (s, 2H), 4.31 (s, 2H), 3.54 (q,
27 N in--1--)11melthYD -1 -rn 422 = 7.2 Hz, 2H), 3.40-3.34(111, 0 ethy1-1,4-dihydro-2 5H), 3.20 (br s, 4H), 2.78 (q, 1.1NO H-benzoldll1,31oxaz citrate I = 15.6 Hz, 4H), 2.60-2.54 (m, in-2-one citrate 2H), 1.90-1.71 (m, 6H), 1.19 (t, = 6.9 Hz, 3H) NMR (300 MHz, lvle0D): 6 7.33-7.12 (m, 8H), 4.51 (s, 2H), 74(4-(ethoxymethyl 4.22 (s, 2H), 3.54 (q, J= 7.2 )-4-phenethylpiperid Hz, 2H), 3.39 (s, 2H), 3.16 (br
28 o o dihydro-2H-benzole s, 4H), 2.78 (q, J = 15.6 Hz, 40 'r NH ][1,3]oxazin-2 -one 4H), 2.59-2.54 (m., 2H), citrate citrate 1.89-1.70 (m, 6H), 1.19 (t, J=
6.9 Hz, 3H).
'FINMR (300 MHz, Me0D): 6 7.64 (s, 1H), 7.42 (d, J= 8.1 Hz, 1H), 7.28-7.12 (m, 6H), 6-((4-(ethoxymethyl 4.28 (s, 2H), 3.53 (q, J= 7.2 )-4-phenethylpiperid
29 N in-] -ypinethyl)benz 410 Hz, 2H), 3.40 (br s, 2H), 3.22 = oldlthiazol-2(3H)-on (br s, 4H), 2.78 (q, J= 15.6 Hz, citrate H e citrate 4H), 2.59-2.21 (m., 2H), 1.90-1.71 (m, 6H), 1.19 (t, J=
6.9 Hz, 3H).
.NMR (300 MHz, Me013): 6 7.38-7.30 (m, 7H), 7.25-7.20 (m, 2H), 7.17-7.13 (m, 3H), 6-((4-(ethoxy(phenyl )meihyl)-4-phenethy 6.94 (dõI = 8.1 Hz, H), 5.33
30 1pipericlin-l-yl)meth 484 (s, 2H), 4.37 (s, 1H), 4.21 (s, y1)-1,4-dihydro-2H- 2H), 3.41-3.36 (m, 2H), 1101 benzo[d][1,31oxazin 3.30-3.26 (m, 2H), 3.10-3.08 citrate -7-one citrate (m, 2H), 2.78 (qõ/ = 15.6 Hz, 4H), 2.67-2.61 (m, 2H), 2.04-1.61 (m, 6H), 1.67 (t, J =

6.9 Hz, 3H).
'H NMR (300 MHz, Me0D): 6 7.41 (d, J = 8.4 Hz, 1H), 7.36 (s, iH), 7.29-7.13 (m, 5H), 6.96 64(441 -e thoxyethyl (d, J' 8.1 Hz, 1H), 5.35 (s, )-4-phenethylpiperid 2H), 4.23 (s, 2H), 3.71-3.66 (m, M-1-yl)methyl)-1,4- 422
31 dihydro-2H-benzo[d 1H), 3.42-3.34 (m, 4H), 3.12 N,L0 ][1,3]oxazin-2-one (br s, 2H), 2.78 J = 15.6 Hz, citrate H
citrate 4H), 2.71-2.50 (m, 2H), 2.03-1.82 (m, 3H), 1.72-1.62 (m, 3H), 1.17-1.13 (m, 6H).
'H NMR (300 MHz, Me0D): 6 7.41 (d, J = 8.7 Hz, 1H), 7.36 6((4-(hydroxymeth (s, 1H), 7.28-7.11 (m, 5H), 6.96 HO y1)-4-phenethylpiper (dõf = 7.8 Hz, 1H), 5.35 (s, idin- 1 -yi)methyl)-1, 380
32 4-dihydro-2H-benzo 2H), 4.24 (s, 2H), 3.53 (s, 2H), L [d] [1,3]oxazin-2-one N, 3.11 (br s, 4H), 2.78 (q, J=
citrate H citrate 15.6 Hz, 4H), 2.60-2.54 (m, 2H), 1.84-1.73 (m, 6H).
114 NMR (300 MHz, Tvle0D):
7.42 (d, J= 8.1 Hz, 1H), 7.37 644-(2-hydraxypro (s, 1H), 7.29-7.13 (rn, 5H), 6.96 HO pan-2-y1)-4-pheneth (d, J= 8.1 Hz, 1H), 5.35 (s,
33 N
ylpiperidin-l-yemet 408 2H), 4.25 (s, 2H), 3.39 (s, 2H), 0 hyl)-1,4-dihydro-2H
3.05 (qõI = 12.9 Hz, 2H), 110 N,.L -benzo[d][1,3]oxazi citrate 2.85-2.68 (m, 6H), 2.08 (t, J
n-2-one citrate 11.7 Hz, 2H), 1.79-1.75 (m, 4H), 1.27 (s, 6H).
NMR (300 MHz, IVIe0D):
7.39-7.32 (m, 2H), 7.30-7.22 1-benzy1-6((4-(etho xymethye-4-pheneth (m, 4H), 7.18-7.11 (m, 611), ylpiperidin-1-yemet 498 7.00 (d, J = 8.4 Hz,
34 NO

hyl)-1,4-dihydro-2H (s, 2H), 5.19 (s, 2H), 4.19 (s, -be LI zo [d][I,3]oxazi 211), 3.54 (q, Jr. 7.2 Hz, 2H), citrate n-2-one citrate 3.45 (s, 211), 3.16 (br s, 4H), 2.78 (q, J= 15.6 Hz, 4H), 2.57-2.52 (m, 2H), 1.87-1.68 (m, 6H), 1.17 (t, J = 6.9 Hz, 3H).
'I-1 NMR (300 MHz, Me0D):
7.42 (d, J= 8.1 Hz, 11-1), 7.33 0 1-((2-oxo-1,4-dihydr (s, 1H), 7.28-7.15 (m, 5H), 6.98 HN o-2H-benzo[d][1,3]o (d, J = 7.8 Hz, 1H), 5.35 (s, xazin-6-yernethy1)-4 393 -phenethylpiperidine 2H), 4.28 (s, 2H), 3.41-3.10 (m, NO -4-carboxarnide 2H), 3.07-3.06 (m, 2H), 2.80 citrate citrate (qõ,1 = 15.6 Hz, 4H), 2.58-2.45 (m, 4H), 1.82-1.68 (m, 4H).
11-1 NMR (300 MHz, Me0D): 6 7.42 (d, J = 7.8 Hz, 1H), 7.35 6-((4-(2-ethoxyprop (s, 1H), 7.29-7.13 (m, 5H), 6.98 an-2-y1)-4-phenethyl (dõf = 7.5 Hz, 1H), 5.35 (s, 36 N piperidin-1-yernethy 436 2H), 4.27 (s, 2H), 3.54-3.42 (m, 1)-1,4 -dihydro -2H- b 4H), 3.11 (br s, 2H), 2.89-2.73 NO enzo[d][1,3]oxazin-citrate H (m, 6H), 2.09 (m, 2H), 2-one citrate 1.84-1.79 (m, 4H), 1.22 (s, 611), 1.15 (t, = 7.2 Hz, 3H).
1-(2-(4-(2H-1,2,3-tri azol-4-yl)phenyl)pro 37 pan-2-y11-4-(ethoxy( N, phenyl)methyl)-4-ph NH enethylpiperidine 1-(2-(4-(2H-tetrazol-o 5-yl)phenyl)propan-38 2-y1)-4-(ethoxy(phen = N yl)rnethyl)-4-phenet ;NH hylpiperidine N'N
6((4-phenethy1-4-(p henoxy(phenyl)meth 39 yl)piperidin-l-yl)me thy11-1H-benzo [ci] [1, 3]oxazin-2(4H)-one 6-((4-(isopropoxy(p henyl)methy1)-4-phe 40 nethylpiperidin-l-y methyl) -1H-benzo[cl 1[1,3]oxazin-2(4H)-H 01le 6-((4-((benzyloxy)(p henyl)methy1)-4-phe 41 0 nethylpiperidin-l-y methyl)- 1H-benzo[d 110 NI ][1,3]oxazin-2(4H)-H
one 6-((4-phenethy1-4-(p henyt(propoxy)ineth 42 yl)piperidin-l-y1tine thyl)-1H-benzo [di [1, ,t 3]oxa-zin-2(4H)-one 6-44-(methoxy(phen yi)tnethy0-4-phenet 43 hylpiperidin-l-yOme thy 1)-1 H-benzo[d] [1, _ 31oxazin-44F11-one NO -6((4-phenethy1-4-(t etrahydro-2H-pyran-2-yl)pipericlin-l-y1) methyl)-1H-benzo[d 1101 N 0 1[1,3]oxazin-2(4H)-one 6-((4-phenethy 1-4-(t etrahydrofuran-2-y1) 45 N piperidin-l-y I)ine thy So 1)- 1H-benzo[d] [1,3]
NO oxazin-2(4H)-one N,N-ditnethy1-1-(C2-o ox o-2,4-dihydro-1H-benzo[d][1,3]oxazin -6-yOrnethyl)-4-phe nethy Ipiperidine-4-c arbo xa Inn&

1((2-oxo-2,4-dihydr H2N o-1H-benzo[d] [1,3]o 47 N xazin-6-yl)methyl)-4 -phenethylpiperidine NO
-4-carboxatnicle (NH 6-((4-(1H-irnidazol-N
2-y1)-4-phenethylpip 48 N eridin-1-y0tnethyl)-6 1H-benzo[d][1,31ox 41111-4-F NO azin-2(4H)-one 6-((4-(5-rnethyl-1,3, N-N
4-thiadiazol -2-y1)-4-pbenethylpiperidin-1 -yl)methyl)-1H-benz 1101 o[d][1,31oxazin-2(4 H)-one N-N
6-((4-(1,3,4-oxadiaz ol-2-y0-4-phenethyl 50 N piperidin-1-yl)methy o 1)-1H-benzo[d][1,3]
411111PP NO oxazin-2(4H)-one 6-(0-phenethy1-4-(p yridirt-4-0-piperidin 51 N -1=-yeinethy 1)- 1H -be fa nzo[d][1,31]oxazin-2( 4111Ijr. N 0 41-1)-one 6-(0-phenethy1-4-ph enyknperidin-1-y 1)m 52 N ethyl)- 111-benzo[d][
1,31oxazin-2(4H)-on 411111rIF e 6-((4-phenethy1-4-(p yridin-2-yl)piperidin 53 N -1-yOmethyl)-1H-be nzo[d][1,31oxazin-2( 4111117 N0 41-)-0[1e, 64(41-phertethy1-4-(p i a 54 N -1-yOrnethyl)-1H-be aze[d][1,3]oxazin-2( N (2' 4H)--one N-((1-((2-oxo-2,4-di 3' hydro-1H-benzo[d][
N
1,3]oxazitt--6-y 1)met hyl)-4-pheaethylpipe 40 N0 ridin-4-yl)methyl)m ethanesurfonamide 64(4-methy1--4-phett ethylpipericlin- 1- yl) 56 N methyl)-1H-benzo1d =
0 111 ,3]oxazin-214H)-N0 011e 6-((4-butyl-4-phenet hylpiperidim-1-y thy1)-1H-benzo[d][ 1, 40 N0 31oxazin-2,(4H)-one N-(0-((2-0X0-2,4-di ):tN
hydro-1H- benzok111 1,3 loxazin-6-yl)met hyl)-4-pheaethylpipe = N'C:LO riclim4-y11methy pac etamide N-(11-1(2-oxo-2,4--di 0 hydro-1H-benzo[c1]1 40 11 59 1,31oxazin-6-y0met = hyl)-4-phenethylpipe H riclim-4--y11methy 1)be azamide 6-q4-(2-hydroxypro HO pan-2-y] )--4--pheneth N ylpiperidia-1-yl)met ? hyl)-1H-benzokl][1, 4111114-1. I\10 3]oxazin-2(4H)-orte 6-t(4-( I -ethoxyethyl )-4-phenethylpiperid 61 N ill- I -y Ornethyl)- I H-NO (101 benzo[d][1,3]oxazin -2(4H)-one 6- q4J2- ethox yprop an-2-y1)-4-phenethyl 62 N piperidin-l-yi)niethy (10 I 1)- 1H-benzo[d][1,3]
oxazin-2(4H)-one 7-((4-(etlioxy met hy1 )-4-phenethylpiperid 63 N in-l-yl)rnethyl)benz = s, o[clli idazo[2,1-lalNJ th iazoie 7-( (4-Kethoxyinethyl )-4-phenethylpiperid 64 N in-1-yl)inethyl)-3,4-o o = dihydro-2H-benzo[b ][1,4]oxitzi it- 2-one 6-(2-(4-(ethoxyrneth y1)-4- phenethy [piper 65 N idin- 1 -yl)propan-2-y = () 1)benzo[d]oxazol-2( 3H)-one 6-t 1-(4-(ethoxymeth y1)-4-phenedaylpiper 66 N ichn-l-y1)ethypbenz io 0 o[d]oxitzol-2(3H)-on ethyl I-( (2-oxo-2,4-di hy dr o-1H- benzo[d] [1,3]o xazin-6-yOrnethyl)-4 40 -phenethylpiperidine o -4-carboxy late 6-q4-(hydroxyrneth HO yi)-4-phenethylpiper 68 N ]din-1 -yl)inethyl)-1 ? H-benzo[d][1,3]oxaz 1\10 in-2(4H)-one *Legend for 4th & 5th columns in Table V is same as for Table I.

Table VI: in vivo testing of compound Nos. 1 to 36 of Table V
ED50 (mg/kg) at 30 min on Compound C57BL/6 mice in Warm-water No. Tail-flick Test (same conditions as Table II) 3 +-I-4 ++
++
6 ++

-F

28 ++

The specific methods, processes, compounds and compositions described herein are representative of preferred and other embodiments, and are exemplary and not intended as limitations on the scope of the invention. Other objects, aspects, and embodiments will occur to those skilled in the art upon consideration of this specification, and are encompassed within the spirit of the invention as defined by the scope of the claims. It will be readily apparent to one skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, or limitation or limitations, which is not specifically disclosed herein as essential. Thus, for example, in each instance herein, in embodiments or examples of the present invention, any of the terms "comprising", "including", containing", "having" etc. are to be read expansively and without limitation. The methods and processes illustratively described herein suitably may be practiced in differing orders of steps, and that they are not necessarily restricted to the orders of steps indicated herein or in the claims. It is also noted that as used herein and in the appended claims, the singular forms "a," an, and the include plural reference, and the plural include singular forms, unless the context clearly dictates otherwise. Under no circumstances may the patent be interpreted to be limited to the specific examples or embodiments or methods specifically disclosed herein. Under no circumstances may the patent be interpreted to be limited by any statement made by any Examiner or any other official or employee of the Patent and Trademark Office unless such statement is specifically and without qualification or reservation expressly adopted in a responsive writing by Applicants.
The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. The terms and expressions that have been employed are used as terms of description and not of limitation, and there is no intent in the use of such terms and expressions to exclude any equivalent of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, it will be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims (20)

WHAT IS CLAIMED IS:
1. A compound selected from compounds having one of the following formulae or a pharmaceutically acceptable salt thereof, wherein, unless otherwise indicated, each chiral compound below is in either the R or the S configuration:
Comp ound Structure Name No.
5-((R or S)-3-(ethoxymethyl)-3-(2-(5-methylt 1 hiophen-2-yl)ethyl)pyrrolidin-1-y1)-2-methy1-6,7-dihydro-5H-cyclopent alblpyridine (S or I \

R)-3-(2-(3-(ethoxymethyl)-3-(2-(3-methylthiophen-2-yl)ethyl)pyrrolidi n-l-yl)propan-2-yl)pyridine (S or R)-3-(2-(3-(ethoxymethyl)-3-(2-(thi ophen-2-yl)ethyl)pyrrolidin-1-y1)pro pan-2-yl)pyridine (S or s R)-5-(2-(3-(2-ethoxypropan-2-y1)-3-4 N (2-(thiophen-2-yl)ethyl)pyrrolidin-1-citrate N I
yl)propan-2-y1)-2-methylpyridine citrate s 5-(24(S&R)-34(S or ' R)-1-ethoxyethyl)-3-(2-(thiophen-2-N
I yl)ethyl)pyrrolidin-1-yl)propan-2-y1) citrate -2-methylpyridine citrate 2-methy1-5-(2-((3R or 6 S)-3-phenethy1-3-(tetrahydrofuran-2 -yl)pyrrolidin-l-yl)propan-2-yl)pyri citrate dine citrate 5-(2-((3R or I \ S)-3-(tetrahydrofuran-2-y1)-3-(2-(thi 7 ophen-2-yl)ethyl)pyrrolidin-1-y1)pro ¨cF3 pan-2-y1)-2-(trifluoromethyl)pyridin 2-methy1-5-(2-((R or S)-3-((S or R)-tetrahydrofuran-2-y1)-3-(2-(thiop hen-2-yl)ethyl)pyrrolidin-1-y1)propa n-2-yl)pyridine 2-methy1-5-(2-((35 or o z R)-3-(tetrahydrofuran-2-y1)-3-(thiop hen-2-ylmethyl)pyrrolidin-1-yl)prop Ní an-2-yl)pyridine 5-(2-((R or S)-3-((S or R)-ethoxy(phenyl)methyl)-3-(2-(thio / I
phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-y1)-2-methylpyridine 5-(2-((R or S)-3-((R or S)-ethoxy(phenyl)methyl)-3-(2-(thio phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-y1)-2-methylpyridine ¨1 5-(2-((R or S)-3-((R or S)-1-ethoxyethyl)-3-(2-(thiophen-2-12 NS"
yl)ethyl)pyrrolidin-l-yl)propan-2-y1) citrate -2-methylpyridine citrate oA_\ 5-(2-((R or S)-3-((S or R)-1-ethoxyethyl)-3-(2-(thiophen-2-13 N S"
yl)ethyl)pyrrolidin-l-yl)propan-2-y1) citrate -2-methylpyridine citrate (R or 14 N) S)-2-methy1-5-(2-(3-(propoxymethyl )-3-(2-(thiophen-2-yl)ethyl)pyrrolidi citrate n-l-yl)propan-2-yl)pyridinecitrate (R or or\I AL S)-1-43-(ethoxymethyl)-1-(2-(6-met 15 ) hylpyridin-3-yl)propan-2-yl)pyrrolid N citrate in-3-yl)methy1)-3-ethyl-1,3-dihydro-2H-benzo1d1imidazo1-2-one citrate (R or OF3c c3 s \ S)-5-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex 16 afluoropropan-2-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-y1)propan-2-y1)-2-methylpyridine 5-(2-((R or cF, s S)-3-(2-ethoxy-1,1,1,3,3,3-hexafluor 17 N opropan-2-y1)-3-(2-(thiophen-2-yl)et hyl)pyrrolidin-1-yl)butan-2-y1)-2-me thylpyridinecitrate (R or ¨0 N O s)-1-((3-(ethoxymethyl)-1-(2-(6-met 18 hylpyridin-3-yl)propan-2-yl)pyrrolid citrate in-3-yl)methyl)-1,3-dihydro-2H-ben zokflimidazol-2-one citrate 2-methy1-5-(2-((3R or S)-3-(tetrahydrofuran-2-y1)-3-(3-(thi S /
c< ophen-2-yl)propyl)pyrrolidin-1-yl)pr opan-2-yl)pyridine (R or 20 ¨`0 S)-5-(2-(3-(ethoxymethyl)-3-(3-(thio s phen-2-yl)propyl)pyrrolidin-1-yl)pro pan-2-y1)-2-methylpyridine (R or 21 0¨\ S)-5-(2-(3-(isopropoxymethyl)-3-(2-N
(thiophen-2-yl)ethyl)pyrrolidin-1-y1) propan-2-y1)-2-methylpyridine 5-(2-((R or N s- S)-3-(isopropoxymethyl)-3-(2-(thiop hen-2-yl)ethyl)pyrrolidin-1-y1)butan -2-y1)-2-methylpyridine (R or S)-1-((3-(ethoxymethyl)-1-(2-(6-met ¨\0 ()NN * hylpyridin-3-yl)propan-2-yl)pyrrolid N citrate in-3-yl)methyl)-3-ethyl-5-fluoro-1,3 -dihydro-2H-benzokflimidazol-2-on ecitrate (R or sy\ S)-2-methy1-5-(1-(2-(6-methylpyridi 24 a n-3-yl)propan-2-y1)-3-(2-(thiophen-2 ¨r citrate -yl)ethyl)pyrrolidin-3-y1)-1,3,4-thiad iazole citrate (R or OF S)-5-(2-(3-(ethoxymethyl)-3-(2-(5-fl 25 N s uorobenzo1blthiophen-2-yl)ethyl)pyr citrate rolidin-l-yl)propan-2-y1)-2-methylp yridine citrate (S or , 26 R)-5-(2-(3-(ethoxymethyl)-3-(thioph N citrate en-2-ylmethyl)pyrrolidin-1-yl)propa n-2-y1)-2-methylpyridine citrate (R or ¨\o S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m / I
27 S ethylpyridin-3-yl)propan-2-yl)pyrrol citrate idin-3-yeethyl)thieno13,2-blpyridine citrate (R or S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m / I
28 N S N ethylpyridin-3-yl)propan-2-yl)pyrrol citrate idin-3-yeethyl)thien012,3-blpyridine citrate (S

R)-1-(2-(3-(ethoxymethyl)-1-(2-(6-methylpyridin-3-yl)propan-2-yl)pyrr Th0 olidin-3-yl)ethyl)-3-ethyl-1,3-dihydr o-2H-benzokflimidazol-2-one (R or is C F3 S)-5-(2-(3-(ethoxymethyl)-3-(2-(5-(t \

citrate rifluoromethyl)thiophen-2-yl)ethyl)p yrrolidin-l-yl)propan-2-y1)-2-methyl pyridine citrate (R or ci s\ F S)-5-(2-(3-(2-(4-chloro-5-fluorothio 31 phen-2-yl)ethyl)-3-(ethoxymethyl)p citrate yrrolidin-l-yl)propan-2-y1)-2-methyl pyridine citrate ci (R or s 32 S)-5-(2-(3-(2-(4-chlorothiophen-3-y1 )ethyl)-3-(ethoxymethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine ci (R or /
S)-5-(2-(3-(2-(4-chlorothiophen-2-y1 )ethyl)-3-(ethoxymethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine 5-(2-((R & S)-3-((S or cF, I s\ F R)-1-ethoxy-2,2,2-trifluoroethyl)-3-( 34 2-(5-fluorothiophen-2-yl)ethyl)pyrro lidin-l-yl)propan-2-y1)-2-methylpyri dine 5-(2-((R or S)-3-((S or / R)-1-ethoxyethyl)-3-(2-(5-fluorothio citrate phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-y1)-2-methylpyridine citrate (R or o_cF3 S)-5-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex \
36 N s----F afluoropropan-2-y1)-3-(2-(5-fluoroth ¨.
I iophen-2-yl)ethyl)pyrrolidin-l-y1)pr 1\1* opan-2-y1)-2-methylpyridine ¨\ 5-(2-((R or S)-3-((R or o \ S)-1-ethoxyethyl)-3-(2-(5-fluorothio dtrate phen-2-yl)ethyl)pyrrolidin-1-y1)prop Nr an-2-y1)-2-methylpyridine citrate (R or HN-e S)-(3-(2-(5-fluorothiophen-2-yl)ethy ¨c 0 38 / I 1)-1-(2-(6-methylpyridin-3-yl)propan N S F
¨..n..,:: citrate -2-yl)pyrrolidin-3-yl)methyl N
isopropylcarbamate citrate (R or HN-eo S)-(3-(2-(5-fluorothiophen-2-yl)ethy 39 I 1)-1-(2-(6-methylpyridin-3-yl)propan N S F
citrate -2-yl)pyrrolidin-3-yl)methyl N
phenylcarbamate citrate isopropyl (S or iPR 40 HN R)-((3-(2-(5-fluorothiophen-2-yl)eth 40 / I y1)-1-(2-(6-methylpyridin-3-yl)propa N S F
citrate n-2-yl)pyrrolidin-3-yl)methyl)carba N
mate citrate phenyl (S or Ph 0 b-t R)-((3-(2-(5-fluorothiophen-2-yl)eth 41 / I y1)-1-(2-(6-methylpyridin-3-yl)propa N S F
¨I n-2-yl)pyrrolidin-3-yl)methyl)carba N
mate (S or iPr 0 R)-1-((3-(2-(5-fluorothiophen-2-yl)e 42 HN / I thyl)-1-(2-(6-methylpyridin-3-yl)pro N S F
citrate pan-2-yl)pyrrolidin-3-yl)methyl)-3-i sopropylurea citrate (S or Ph ,0 R)-1-((3-(2-(5-fluorothiophen-2-yl)e HN
43 / I thyl)-1-(2-(6-methylpyridin-3-yl)pro N S F
citrate pan-2-yl)pyrrolidin-3-yl)methyl)-3-p henylurea citrate 44 (R or HO
S)-(3-(4-fluorophenethyl)-1-(pyridin citrate -3-ylmethyl)pyrrolidin-3-yl)methano 1 citrate 45 (R or S)-3-43-(ethoxymethyl)-3-(4-fluoro N In.'F citrate phenethyl)pyrrolidin-l-yl)methyl)-5-N
fluoropyridine citrate 46 (R or S)-3-(ethoxymethyl)-3-(4-fluorophe nethyl)-N-(pyridin-3-yl)pyrrolidine-1-carboxamide 47 (R or F S)-3-(2-(3-(ethoxymethyl)-3-(4-fluor ophenethyl)pyrrolidin-l-yl)ethyl)pyr N
idine 0 (R or S)-3,3'4(3-(ethoxymethyl)-3-(4-fluo I I
N N rophenethyl)pyrrolidin-l-yl)methyle ne)dipyridine 49 (R or S)-N-(3-(ethoxymethyl)-3-(4-fluoro HN-rj: phenethyl)pyrrolidin-l-yl)pyridin-3-N
amine 50 3-(1-((R or F S)-3-(ethoxymethyl)-3-(4-fluorophe F3Ct nethyl)pyrrolidin-1-y1)-2,2,2-trifluor oethyl)pyridine 51 (R or S)-3,5-dichloro-4-((3-(ethoxymethyl N CI
CI )-3-(4-fluorophenethyl)pyrrolidin-1-yl)methyl)pyridine 52 (R or N CN S)-4-(2-(3-(ethoxymethyl)-1-(pyridi n-3-ylmethyl)pyrrolidin-3-yl)ethyl)b enzonitrile 53 F (R or S)-3-((3-(ethoxymethyl)-3-(4-fluoro phenethyl)pyrrolidin-l-yl)methyl)iso nicotinonitrile CN
54 F (R or S)-3-((3-(ethoxymethyl)-3-(4-fluoro phenethyl)pyrrolidin-l-yl)methyl)pi colinonitrile N \
0 (R or S)-5-((3-(ethoxymethyl)-3-(4-fluoro phenethyl)pyrrolidin-l-yl)methyl)-2-methoxypyridine 56 (R or ¨\

S)-5-((3-(ethoxymethyl)-3-(4-fluoro F
N
b phenethyl)pyrrolidin-l-yl)methyl)-2-, methoxyisonicotinonitrile ) F (R or S)-3-((3-(ethoxymethyl)-3-(4-fluoro N
phenethyl)pyrrolidin-l-yl)methyl)pi H2N1,) N
0 colinamide ) F 5-((R or S)-3-(ethoxymethyl)-3-(4-fluorophe nethyl)pyrrolidin-1-y1)-6,7-dihydro-. ri ON
0 1,7-naphthyridin-8(5H)-one 59 5-((R or F
S)-3-(ethoxymethyl)-3-(4-fluorophe N nethyl)pyrrolidin-1-y1)-6,6-dimethyl I
-6,7-dihydro-1,7-naphthyridin-8(5H) o -one 60 (R or ¨\

S)-4-(2-(1-(di(pyridin-3-yl)methyl)-CN
N
(*) 3-(ethoxymethyl)pyrrolidin-3-yl)eth N N
yl)benzonitrile 61 ¨\
0 (R or F
N S)-2-(3-(ethoxymethyl)-3-(4-fluorop IN
henethyl)pyrrolidin-1-y1)-1-(6-meth ylpyridin-3-yl)ethan-1-one 0 (R or S)-2-(3-(ethoxymethyl)-3-(4-fluorop henethyl)pyrrolidin-l-y1)-2-methy1-1 N
-(6-methylpyridin-3-yl)propan-1-one 0 (R or N N S)-2-(3-(ethoxymethyl)-3-(2-(5-fluor opyridin-2-yl)ethyl)pyrrolidin-1-y1)-N
1-(6-methylpyridin-3-yl)ethan-1-one 64 (R or S)-2-(3-(ethoxymethyl)-3-(2-(5-fluor = N
0 opyridin-2-yl)ethyl)pyrrolidin-1-y1)-N 2-methy1-1-(6-methylpyridin-3-yl)pr opan-l-one 65 (R or S)-4-(2-(3-(oxetan-3-y1)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)ethyl)ben zonitrile 66 OL\cIF (R or S)-3-43-(4-fluorophenethyl)-3-(oxet an-3-yl)pyrrolidin-1-yl)methyl)pyrid ine (R or S)-4-(2-(1-(2-(6-methylpyridin-3-y1) propan-2-y1)-3-(oxetan-3-yepyrrolid in-3-yl)ethyl)benzonitrile 68 (R or S)5-(3-(3-(4-fluorophenethyl)-3-(ox etan-3-yl)pyrrolidin-1-yl)oxetan-3-y1 )-2-methylpyridine 69 F3c õ (R or kar3 /
N S)-5-(2-(3-(1,1,1,3,3,3-hexafluoro-2-methoxypropan-2-y1)-3-(2-(thiophen -2-yl)ethyl)pyrrolidin-1-y1)propan-2-y1)-2-methylpyridine 70 (R or F3c cF3 s ' S)-5-((3-(2-ethoxy-1,1,1,3,3,3-hexaf luoropropan-2-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-l-yl)methyl)-2-m ethylpyridine 71 (R or F3c cF3 s ' S)-3-43-(2-ethoxy-1,1,1,3,3,3-hexaf luoropropan-2-y1)-3-(2-(thiophen-2-nr yl)ethyl)pyrrolidin-l-yl)methyl)pyri dine 72 (R or 0 "
S)-5-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex afluoropropan-2-y1)-3-(4-fluorophen ethyl)pyrrolidin-l-yl)propan-2-y1)-2-methylpyridine 73 (R or S)-5-(2-(3-(4-fluorophenethyl)-3-(1, 1,1,3,3,3-hexafluoro-2-methoxyprop an-2-yl)pyrrolidin-1-yepropan-2-y1) -2-methylpyridine F3C õ
74 HO L'-3 (R or S ) - 1 , 1,1,3,3,3-hexafluoro-2-(3-(4-flu orophenethyl)-1-(2-(6-methylpyridin -3-yl)propan-2-yl)pyrrolidin-3-yl)pr opan-2-ol 75 (R or F3C " õ3 S)-5-((3-(2-ethoxy-1,1,1,3,3,3-hexaf luoropropan-2-y1)-3-(4-fluorophenet hyl)pyrrolidin-l-yl)methyl)-2-methy 1pyridine 76 F3c 0 (R or S)-3-43-(2-ethoxy-1,1,1,3,3,3-hexaf luoropropan-2-y1)-3-(4-fluorophenet hyl)pyrrolidin-l-yl)methyl)pyridine 77 (R or S)-4-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex afluoropropan-2-y1)-1-(2-(6-methylp yridin-3-yl)propan-2-yl)pyrrolidin-3 -yl)ethyl)benzonitrile 78 (R or F3C CF_ CN

S)-4-(2-(3-(1,1,1,3,3,3-hexafluoro-2-N
methoxypropan-2-y1)-1-(2-(6-methyl pyridin-3-yl)propan-2-yl)pyrrolidin-3-yl)ethyl)benzonitrile 79 (R or S)-4-(2-(3-(1,1,1,3,3,3-hexafluoro-2-c. N
hydroxypropan-2-y1)-1-(2-(6-methyl pyridin-3-yl)propan-2-yl)pyrrolidin-3-yl)ethyl)benzonitrile 80 F3c CF3 CN (R or S)-4-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex afluoropropan-2-y1)-1-((6-methylpyr idin-3-yl)methyl)pyrrolidin-3-yl)eth yl)benzonitrile 81 (R or S)-4-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex afluoropropan-2-y1)-1-(pyridin-3-y1 methyl)pyrrolidin-3-yl)ethyl)benzon itrile (R or F
F¨(0 S)-5-(2-(3-((difluoromethoxy)methy 82 / I 1)-3-(2-(thiophen-2-yl)ethyl)pyrrolid N s in-l-yl)propan-2-y1)-2-methylpyridi citrate ne citarte (R or S)-3-43-(ethoxymethyl)-1-(2-(6-met 83 hylpyridin-3-yl)propan-2-yl)pyrrolid citrate in-3-yl)methyl)-3H-imidazo[4,5-clp &N
yridine citarte (R or S)-1-43-(ethoxymethyl)-1-(2-(6-met 41k0¨\ hylpyridin-3-yl)propan-2-yl)pyrrolid ) N citrate in-3-yl)methyl)-3-ethyl-5,6-difluoro-1,3-dihydro-2H-benzokflimidazol-2-&N
one citarte (R or S)-1-43-(ethoxymethyl)-1-(2-(6-met 85 hylpyridin-3-yl)propan-2-yl)pyrrolid --j\/ citrate in-3-yl)methyl)-1H-imidazo14,5-clp yridine citrate 5-(2-((S or R)-3-((R&
N
S)-ethoxy(pyridin-2-yl)methyl)-3-(2 86 -(thiophen-2-yl)ethyl)pyrrolidin-1-y1 )propan-2-y1)-2-methylpyridine citrate citrate 5-(2-((R or S)-3-((S or o R)-isochroman-l-y1)-3-(2-(thiophen-/ I
2-yl)ethyl)pyrrolidin-1-y1)propan-2---r citrate y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((R or o S)-isochroman-1-y1)-3-(2-(thiophen-/ I
2-yl)ethyl)pyrrolidin-1-y1)propan-2-citrate y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((S or o R)-isochroman-l-y1)-3-(2-(thiophen-/
2-yl)ethyl)pyrrolidin-1-y1)butan-2-y1 citrate )-2-methylpyridine citrate 5-(2-((R or F S)-3-((S&R)-1-ethoxy-2,2,2-trifluor 90 oethyl)-3-(2-(5-fluorothiophen-2-y1) ethyl)pyrrolidin-l-yl)butan-2-y1)-2-N
methylpyridine 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth 91 /¨N
ylpyridin-3-yl)propan-2-yepyrrolidi citrate n-3-yl)ethyl)-1H-imidazo14,5-clpyri dine citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth \--92 rN
ylpyridin-3-yl)propan-2-yl)pyrrolidi citarte n-3-yl)ethyl)-1,3-dihydro-2H-imidaz 1 1, o[4,5-clpyridin-2-one citrate 5-(2-((R or F3c S)-3-(2-ethoxy-1,1,1,3,3,3-hexafluor s F
opropan-2-y1)-3-(2-(5-fluorothiophe n-2-yl)ethyl)pyrrolidin-1-y1)butan-2-N
y1)-2-methylpyridine 5-(2-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl o )-3-((R or S)-isochroman-l-yl)pyrrolidin-1-y1) citrate propan-2-y1)-2-methylpyridine N1*-citrate 5-(2-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl o )-3-((S or R)-isochroman-l-yl)pyrrolidin-1-y1) citrate propan-2-y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((R or S)-ethoxy(phenyl)methyl)-3-(2-(5-fl I s\ F

96 uorothiophen-2-yl)ethyl)pyrrolidin-1 citrate -yl)butan-2-y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((R or ¨\o S)-ethoxy(phenyl)methyl)-3-(2-(5-fl uorothiophen-2-yl)ethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine citrate citrate 5-(2-((R or S)-3-((S or R)-ethoxy(phenyl)methyl)-3-(2-(5-fl 98 /s I uorothiophen-2-yl)ethyl)pyrrolidin-1 citrate -yl)propan-2-y1)-2-methylpyridine citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth C))\--NH
¨00 'N. ylpyridin-3-yl)propan-2-yepyrrolidi n-3-yl)ethyl)-5,6-difluoro-1,3-dihydr F citrate o-2H-benzoldlimidazol-2-one citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth o ylpyridin-3-yl)propan-2-yepyrrolidi 100 /-N4k n-3-yl)ethyl)-5,6-difluoro-3-isobutyl ¨1F citrate -1,3-dihydro-2H-benzoldlimidazol-2 -one citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth o ylpyridin-3-yl)propan-2-yepyrrolidi 'N*
101 n-3-yl)ethyl)-3-ethyl-5,6-difluoro-1, carate 3-dihydro-2H-benzoldlimidazol-2-o ne citrate ¨Xo (S)-4-((3-(ethoxymethyl)-3-(2-(thiop 102 hen-2-yl)ethyl)pyrrolidin-1-y1)methy 1)pyridine H3PO4 salt 5-(2-((R or / \
N S)-3-((S&R)-ethoxy(pyridin-2-yl)me o 103 / I thyl)-3-(2-(5-fluorothiophen-2-yl)eth N S F
citrate yl)pyrrolidin-1-yl)propan-2-y1)-2-me thylpyridine citrate 5-(2-((R or S)-3-((S or I F
0 R)- 1-ethoxyethyl)-3-(2-(5-fluorothio 104 citrate phen-2-yl)ethyl)pyrrolidin-1-y1)buta n-2-y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((R or F
0 105 S)-1-ethoxyethyl)-3-(2-(5-fluorothio citrate phen-2-yl)ethyl)pyrrolidin-1-y1)buta n-2-y1)-2-methylpyridine citrate (S or 0 N R)-4-((3-(2-(5-fluorothiophen-2-yl)e 106 thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)mor pholine 107 (S or R)-1-ethy1-3-43-(2-(5-fluorothiophe n-2-yl)ethyl)-1-(2-(6-methylpyridin-,Ni, N S F
ovate 3-yl)propan-2-yl)pyrrolidin-3-yl)met hyl)-1,3-dihydro-2H-benzo kflimidaz ol-2-one citrate (R or / S)-5-(2-(3-(2-(4,5-dimethylthiophen 108 -2-yl)ethyl)-3-(ethoxymethyl)pyrroli citrate din-1-yl)propan-2-y1)-2-methylpyrid ine citrate (R or S)-N-((3-(2-(5-fluorothiophen-2-yl)e 109 LN>
s F thyl)-1-(2-(6-methylpyridin-3-yl)pro citrate pan-2-yl)pyrrolidin-3-yl)methyl)met hanesulfonamide citrate (R or \Q S)-N-((3-(2-(5-fluorothiophen-2-yl)e 00s.

F thyl)-1-(2-(6-methylpyridin-3-yl)pro +CI_ citrate pan-2-yl)pyrrolidin-3-yl)methyl)-4-N
methylbenzenesulfonamide citrate 111 (S or F)=\
R)-4-fluoro-N-((3-(2-(5-fluorothioph en-2-yl)ethyl)-1-(2-(6-methylpyridin N s F
'trate -3-yl)propan-2-yl)pyrrolidin-3-yl)me thyl)benzenesulfonamide citrate (S & R)-5-((R or o l S)-3-(2-(5-fluorothiophen-2-yl)ethyl j / \
112 s F )-1-(2-(6-methylpyridin-3-yl)propan citrate -2-yl)pyrrolidin-3-yl)oxazolidin-2-o ne citrate (R or H NeN, N
S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 113 S )ethyl)-3-(1H-imidazol-2-yepyrrolid F
citrate in-1-yl)propan-2-y1)-2-methylpyridi ne citrate (R or N
S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 114 )ethyl)-3-(1-methyl-1H-imidazol-2-y citrate 1)pyrrolidin-1-yflpropan-2-y1)-2-met hylpyridine citrate (R or sN
S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 115 )ethyl)-3-(4H-1,2,4-triazol-3-yl)pyrr olidin-1-yflpropan-2-y1)-2-methylpy ridine (R or > \o_\
S)-5-(2-(3-((cyclopropylmethoxy)m N) 116 ethyl)-3-(2-(5-fluorothiophen-2-yl)et citrate hyl)pyrrolidin-l-yflpropan-2-y1)-2-N
methylpyridine citrate (R or H2N / \ S)-3-(2-(5-fluorothiophen-2-yl)ethyl s 117 F )-1-(2-(6-methylpyridin-3-yl)propan +0 citrat -2-yl)pyrrolidine-3-carboxamide e N
citrate (R or I s\ F S,E)-3-(2-(5-fluorothiophen-2-yl)eth 118 N yl)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidine-3-carbaldehyde citrate 0-methyl oxime citrate (S or HN / R)-((3-(2-(5-fluorothiophen-2-yl)eth 119 y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidin-3-yl)methyl)sulfa moyl amine 120 (S or R)-((3-(2-(5-fluoro-thiophen-2-yl)ethyl) / I -1-(2-(6-methylpyridin-3-yl)propan-N S F
citrate 2-yl)pyrrolidin-3-y1)(pyridin-2-yl)m ethyl)sulfamoyl amine 121 (S or R)-0+0 ((3-(2-(5-fluorothiophen-2-yl)ethyl)-HN
1-(2-(6-methylpyridin-3-yl)propan-2 -yl)pyrrolidin-3-yl)methyl)sulfamoyl dimethyl amine 122 F (R or NH S)-((3-(2-(5-fluorothiophen-2-yl)eth 0+0 HN, y1)-1-(2-(6-methylpyridin-3-yl)propa s n-2-yl)pyrrolidin-3-yl)methyl)sulfa 'trate moyl 4-fluorophenylamine citrate 123 (R or HN
S)-((3-(2-(5-fluorothiophen-2-yl)eth ;S*
O'HsN y1)-1-(2-(6-methylpyridin-3-yl)propa /
N S F
n-2-yl)pyrrolidin-3-yl)methyl)sulfa ¨icitrate moyl 4-methylphenyl amine CI
(R or HNS.Q CI S)-((3-(2-(5-fluorothiophen-2-yl)eth / y1)-1-(2-(6-methylpyridin-3-yl)propa N S F
n-2-yl)pyrrolidin-3-yl)methyl)sulfa Exact Mass: 584.12 moyl 2,4-dichloro phenyl amine tPSA: 73.8 CLogP: 6.67 125 (S or 40 R)-4-methyl-N-((1-(pyridin-3-ylmet ol=o HN \ hyl)-3-(2-(thiophen-2-yl)ethyl)pyrrol citrate idin-3-yl)methyl)benzenesulfonamid L-0 e citrate 126 (S or R)-N-((3-(2-(4,5-dimethylthiophen-2-yl)ethyl)-1-(2-(6-methylpyridin-3-A
/ I
N S yl)propan-2-yl)pyrrolidin-3-yl)meth citrate y1)-4-methylbenzenesulfonamide citrate 127 (S or 1401 R)-N-((3-(4-fluorophenethyl)-1-(2-( o==o HJjfF 6-methylpyridin-3-yl)propan-2-yl)py citrate rrolidin-3-yl)methyl)-4-methylbenze nesulfonamide citrate (R or S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m I \
128 o S ethylpyridin-3-yl)propan-2-yl)pyrrol Tiii idin-3-yeethyl)thienol3,4-blpyrazin (R or S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m I F
129 ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yeethyl)-7-fluorothieno[3,4-b 1pyrazine 1-4R or S)-1-(2-(6-methylpyridin-3-yl)propa 130 n-2-y1)-3-(2-(thiophen-2-yl)ethyl)py N s--rrolidin-3-y1)-3,4-dihydro-1H-pyran 0[4,3-c]pyridine 5-(2-((3R or S)-3-(6-fluoroisochroman-1-y1)-3-(2 / I
-(thiophen-2-yl)ethyl)pyrrolidin-1-y1 )propan-2-y1)-2-methylpyridine 5-(2-((3R or FIN/
-N
S)-3-((4,5-dihydro-1H-imidazol-2-y1 132 )(ethoxy)methyl)-3-(2-(thiophen-2-y s¨

flethyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine (R or 0-\ S)-5-(2-(3-(((4,5-dihydro-1H-imidaz 133 c) \-0 ol-2-yl)methoxy)methyl)-3-(2-(thiop hen-2-yl)ethyl)pyrrolidin-1-y1)propa n-2-y1)-2-methylpyridine 1\1 5-(2-((S or R)-3-((S or ¨\o R)-ethoxy(pyridin-3-yl)methyl)-3-(2 S -(thiophen-2-yl)ethyl)pyrrolidin-1-y1 N )propan-2-y1)-2-methylpyridine 5-(2-((S or R)-3-((S or O N
R)-ethoxy(pyridin-2-yl)methyl)-3-(2 -(thiophen-2-yl)ethyl)pyrrolidin-1-y1 )propan-2-y1)-2-methylpyridine N
/
5-(2-((3R or ¨X0 S)-3-(ethoxy(pyridin-4-yl)methyl)-3 -(2-(thiophen-2-yl)ethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine (R or I S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m 137 N s N
ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yeethyl)thieno[2,3-clpyridine (R or I N S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yeethyl)thieno[3,2-clpyridine (R or S)-6-(2-(3-(ethoxymethyl)-1-(2-(6-m N S N ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yeethyl)thien0[2,3-blpyrazin (R or S)-5-(2-(3-(2-(4,5-difluorothiophen-F
140 2-yl)ethyl)-3-(ethoxymethyl)pyrrolid in-l-yl)propan-2-y1)-2-methylpyridi ne (R or NC
S)-4-(2-(3-(ethoxymethyl)-1-(2-(6-m s 141 ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethyl)thiophene-3-carbonit rile (R or s 142 S)-5-(2-(3-(ethoxymethyl)-3-(2-(4-fl uorothiophen-3-yl)ethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine (R or /
143 S)-5-(2-(3-(ethoxymethyl)-3-(2-(4-fl uorothiophen-2-yl)ethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine (R or CN
\ S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m 144 ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethyl)thiophene-3-carbonit rile _N 1-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl 145 )-1-(2-(6-methylpyridin-3-yl)propan S'NF
-2-yl)pyrrolidin-3-y1)-3,4-dihydro-1 H-pyranol4,3-clpyridine 5-(2-((3R or S)-3-(6-fluoroisochroman-1-y1)-3-(2 146 -(5-fluorothiophen-2-yl)ethyl)pyrroli /
din-1-yl)propan-2-y1)-2-methylpyrid ine 5-(2-((3R or o 147 / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F )-3-(isochroman-1-yl)pyrrolidin-1-y1 ¨I )propan-2-y1)-2-methylpyridine N
HI\l/.
-N 5-(2-((3R or ¨\o S)-3-((4,5-dihydro-1H-imidazol-2-y1 148 6 NF\ e )(ethoxy)methyl)-3-(2-(5-fluorothiop --, hen-2-yl)ethyl)pyrrolidin-1-y1)propa N
n-2-y1)-2-methylpyridine (R or H
co N
S)-5-(2-(3-(((4,5-dihydro-1H-imidaz b 149 0, ol-2-yl)methoxy)methyl)-3-(2-(5-flu N S F
orothiophen-2-yl)ethyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine 5-(2-((S or R)-3-((R or / \N
¨\ S)-ethoxy(pyridin-3-yl)methyl)-3-(2 o 0, -(5-fluorothiophen-2-yl)ethyl)pyrroli N S F
¨I din-1-yl)propan-2-y1)-2-methylpyrid N
ine 5-(2-((S or R)-3-((R or -\ N S)-ethoxy(pyridin-2-yl)methyl)-3-(2 o 151 \ CJ -(5-fluorothiophen-2-yl)ethyl)pyrroli N F
¨r din-1-yl)propan-2-y1)-2-methylpyrid N
ine N) 5-(2-((S or R)-3-((R or c)_c ¨\
S)-ethoxy(pyridin-4-yl)methyl)-3-(2 152 N \
S"---F -(5-fluorothiophen-2-yl)ethyl)pyrroli din-1-yl)propan-2-y1)-2-methylpyrid ine (S or , R)-5-(2-(3-(ethoxymethyl)-3-((5-flu orothiophen-2-yl)methyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine 5-(2-((3R or /=-\
S)-3-(ethoxy(1-methy1-1H-imidazol-I \ F
154 `(:) 2-yl)methyl)-3-(2-(5-fluorothiophen-2-yl)ethyl)pyrrolidin-1-y1)propan-2-y1)-2-methylpyridine 8-((R or /=\
NN S)-3-(2-(5-fluorothiophen-2-yl)ethyl s\ F
155 )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-y1)-5,6-dihydro-8 H-imidazo12,1-011,41oxazine 5-(2-((3R or /=\ S)-3-(ethoxy(1H-imidazol-2-yl)meth HN ,,N
F
156 y1)-3-(2-(5-fluorothiophen-2-yl)ethyl )pyrrolidin-l-yl)propan-2-y1)-2-meth ylpyridine 7-((R or r\-IN S)-3-(2-(5-fluorothiophen-2-yl)ethyl oo" F
157 )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-y1)-5H,7H-imidaz o11,2-cloxazol-5-one 3-ethy1-5-((R or c;,c)N \ F
158 S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)oxazolidin-2-o ne HO (R = or S)-2-(1-(2-(6-methylpyridin-3-yl)pro pan-2-y1)-3-(2-(thiophen-2-yl)ethyl) pyrrolidin-3-yl)propan-2-ol CF3 (R or HO

S)-1,1,1,3,3,3-hexafluoro-2-(1-(2-(6-160 methylpyridin-3-yl)propan-2-y1)-3-( 2-(thiophen-2-yl)ethyl)pyrrolidin-3-N
yl)propan-2-ol (R or CF3 s S)-5-(2-(3-(1-ethoxy-2,2,2-trifluoroe 161 N thyl)-3-(2-(thiophen-2-yeethyl)pyrro lidin-l-yl)propan-2-y1)-2-methylpyri dine HO CF3 s (R or S)-2,2,2-trifluoro-1-(1-(2-(6-methylp 162 N yridin-3-yepropan-2-y1)-3-(2-(thiop hen-2-yl)ethyl)pyrrolidin-3-yl)ethan-1\1 1-ol OH
HO) s (R or 163 S)-1-(1-(2-(6-methylpyridin-3-yl)pro pan-2-y1)-3-(2-(thiophen-2-yl)ethyl) pyrrolidin-3-yl)ethane-1,2-diol OH
(R or s 164 S)-2-ethoxy-2-(1-(2-(6-methylpyridi n-3-yl)propan-2-y1)-3-(2-(thiophen-2 -yl)ethyl)pyrrolidin-3-yl)ethan-1-ol NH2 (R or S S)-2-ethoxy-2-(1-(2-(6-methylpyridi 165 n-3-yl)propan-2-y1)-3-(2-(thiophen-2 -yl)ethyl)pyrrolidin-3-yl)ethan-1-am ine 0 (R or S
S)-5-(2-(3-(1,4-dioxan-2-y1)-3-(2-(th iophen-2-yl)ethyl)pyrrolidin-1-y1)pr I opan-2-y1)-2-methylpyridine rNH
0 S (R or 167 S)-2-(1-(2-(6-methylpyridin-3-yl)pro pan-2-y1)-3-(2-(thiophen-2-yl)ethyl) pyrrolidin-3-yl)morpholine 5-(2-((R or F S)-34(S)-ethoxyfluoromethyl)-3-(2-/ I
168 S F (5-fluorothiophen-2-yl)ethyl)pyrroli din-1-yl)propan-2-y1)-2-methylpyrid ine 5-(2-((R or o S)-34(R)-ethoxyfluoromethyl)-3-(2-) 169 N S F (5-fluorothiophen-2-yl)ethyl)pyrroli din-1-yl)propan-2-y1)-2-methylpyrid ine (R or S)-5-(2-(3-(1-ethoxycyclopropy1)-3-¨1A¨\--0, 170 S F (2-(5-fluorothiophen-2-yl)ethyl)pyrr olidin-1-yl)propan-2-y1)-2-methylpy ridine (R or o S)-5-(2-(3-(2-ethoxypropan-2-y1)-3-( 171 N SF 2-(5-fluorothiophen-2-yl)ethyl)pyrro TÇ lidin-l-yl)propan-2-y1)-2-methylpyri dine CN 2-ethoxy-2-4R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl 172 N s"-"'F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)acetonitrile (R or NC--\0 S)-2-((3-(2-(5-fluorothiophen-2-yl)et / I
173 N hyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methoxy)ac etonitrile (R or -Tho S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m / I
174 S CN ethylpyridin-3-yl)propan-2-yl)pyrrol Thn idin-3-yl)ethyl)thiophene-2-carbonit rile (R or 1-121\140 S)-(3-(2-(5-fluorothiophen-2-yl)ethy 175 / 1)-1-(2-(6-methylpyridin-3-yl)propan N S F
iÇ
-2-yl)pyrrolidin-3-yl)methyl carbamate (R or H2N-eo S)-2-(3-(2-(5-fluorothiophen-2-yl)et 176 N / I F hyl)-1-(2-(6-methylpyridin-3-yl)pro S
pan-2-yl)pyrrolidin-3-yl)propan-2-y1 carbamate (R or HN-e S)-2-(3-(2-(5-fluorothiophen-2-yl)et ¨c 0 hyl)-1-(2-(6-methylpyridin-3-yl)pro S
pan-2-yl)pyrrolidin-3-yl)propan-2-y1 isopropylcarbamate (R or HN430 S)-2-(3-(2-(5-fluorothiophen-2-yl)et hyl)-1-(2-(6-methylpyridin-3-yl)pro S
pan-2-yl)pyrrolidin-3-yl)propan-2-y1 phenylcarbamate (R or H2N-e03(F S)-difluoro(3-(2-(5-fluorothiophen-2 179 -yl)ethyl)-1-(2-(6-methylpyridin-3-y N S F
1)propan-2-yl)pyrrolidin-3-yl)methyl carbamate (R or HN-e F S)-difluoro(3-(2-(5-fluorothiophen-2 F
180 ) N S F -yl)ethyl)-1-(2-(6-methylpyridin-3-y 1)propan-2-yl)pyrrolidin-3-yl)methyl isopropylcarbamate (R or 181 / S)-difluoro(3-(2-(5-fluorothiophen-2 N s F
-yl)ethyl)-1-(2-(6-methylpyridin-3-y 1)propan-2-yl)pyrrolidin-3-yl)methyl phenylcarbamate (R or H2N¨</F 03C F3 S)-1,1,1,3,3,3-hexafluoro-2-(3-(2-(5-N S F fluorothiophen-2-yl)ethyl)-1-(2-(6-m ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yepropan-2-y1 carbamate (R or A
+
S)-1,1,1,3,3,3-hexafluoro-2-(3-(2-(5-183 IN u3 fluorothiophen-2-yl)ethyl)-1-(2-(6-m / I
N S F
ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yepropan-2-y1 isopropylcarbamate (R or S)-1,1,1,3,3,3-hexafluoro-2-(3-(2-(5-HN4)03C c3 184 fluorothiophen-2-yl)ethyl)-1-(2-(6-m N S F
ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yepropan-2-y1 phenylcarbamate (S)-1-((R or H2N40_( S)-3-(2-(5-fluorothiophen-2-yl)ethyl 185 \ )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl carbamate (R)-1-((R or H2N-eo S)-3-(2-(5-fluorothiophen-2-yl)ethyl 186 / I )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)ethyl carbamate (S)-1-((R or 187 A,N
N S F S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl isopropylcarbamate (R)-1-((R or _74 0 S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S"--NF )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl isopropylcarbamate (S)-1-((R or HN430 S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan S
-2-yl)pyrrolidin-3-yl)ethyl -N-phenylcarbamate (R)-1-((R or HN40 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 190 )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl -N-phenylcarbamate (S)-fluoro((R or H2N40 F S)-3-(2-(5-fluorothiophen-2-yl)ethyl 191 I N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl carbamate H 2 N4 F (R)-fluoro((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl I
N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl carbamate (S)-fluoro((R or HN¨e F S)-3-(2-(5-fluorothiophen-2-yl)ethyl 193 ) N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl isopropylcarbamate (R)-fluoro((R or HN¨e ,µF S)-3-(2-(5-fluorothiophen-2-yl)ethyl ¨c 0 =
194 / )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)methyl isopropylcarbamate (S)-fluoro((R or HN¨eo F S)-3-(2-(5-fluorothiophen-2-yl)ethyl 195 / )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)methyl phenylcarbamate (R)-fluoro((R or HN¨eo j S)-3-(2-(5-fluorothiophen-2-yl)ethyl 196 / )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)methyl phenylcarbamate (R)-2,2,2-trifluoro-1-((R or u2N¨eo CF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 197 / I N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl carbamate (S)-2,2,2-trifluoro-1-((R or H2N-e0 .z.c F3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 198 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl carbamate (R)-2,2,2-trifluoro-1-((R or HN4 CF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 199 / I N s F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl isopropylcarbamate (S)-2,2,2-trifluoro-14(R or AIN-e0 p F3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 200 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl isopropylcarbamate (R)-2,2,2-trifluoro-1-((R or HN-eo CF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 201 d )-1-(2-(6-methylpyridin-3-yl)propan N S F
Thn -2-yl)pyrrolidin-3-yl)ethyl phenylcarbamate (S)-2,2,2-trifluoro-1-((R or HN-e p F3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl o 202 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl phenylcarbamate 1-fluoro-1-((R or 203 :
/ S)-3-(2-(5-fluorothiophen-2-yl)ethyl I
N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl carbamate 1-fluoro-1-((R or HN40 CH3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl \¨es)F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl isopropylcarbamate 1-fluoro-14(R or HN40 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 205 d N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl phenylcarbamate 1,1,1-trifluoro-2-((R or H2N-eo cHF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl N s )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)propan-2-y1 carbamate 1,1,1-trifluoro-2-((R or HN-eo cH,F S)-3-(2-(5-fluorothiophen-2-yl)ethyl tc3 207 c) )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)propan-2-y1 isopropylcarbamate 1,1,1-trifluoro-2-((R or HN4)0 cidF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 208 )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)propan-2-y1 phenylcarbamate 1-(1,2,2,2-tetrafluoro-1-((R or H2N-fN F
S)-3-(2-(5-fluorothiophen-2-yl)ethyl / I
N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-isopropy1-3-(1,2,2,2-tetrafluoro-1-HN-e F ((R or 210 / I S F S)-3-(2-(5-fluorothiophen-2-yl)ethyl N
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-pheny1-3-(1,2,2,2-tetrafluoro-1-(( 211 d HN-ECF_CF, or \¨es-1F S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea isopropyl ((S)-1-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan Pr `0 0/N -2-yl)pyrrolidin-3-yl)ethyl)carbamat N s F
isopropyl (( 1 S)- 1-(3-(2-(5-fluorothiophen-2-y1 )ethyl)-1-(2-(6-methylpyridin-3-yl)p ropan-2-yl)pyrrolidin-3-yl)ethyl)car bamate isopropyl ((R)-1-((R or Pr 0 , HN " S)-3-(2-(5-fluorothiophen-2-yl)ethyl 213 / I )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)ethyl)carbamat cA 03188131 2022-12-22 isopropyl ((R)-fluoro((R or iPrõ0 0¨(< S)-3-(2-(5-fluorothiophen-2-yl)ethyl HN "
214 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)methyl)carbam ate isopropyl ((S)-fluoro((R or iPrõ0 S)-3-(2-(5-fluorothiophen-2-yl)ethyl HN
215 / I N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)carbam ate isopropyl ((S)-2,2,2-trifluoro-1-((R
iPr p or CF
216 ) N S F S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)carbamat isopropyl ((R)-2,2,2-trifluoro-1-4R
iPrx cF3 or HN
S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)carbamat isopropyl (R or iPr, 40H c HN3 CH3 S)-(2-(3-(2-(5-fluorothiophen-2-yl)et N S F hyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)propan-2-y1 )carbamate isopropyl (1,1,1-trifluoro-2-((R or 'Prbtc? Cõ S)-3-(2-(5-fluorothiophen-2-yl)ethyl 219 N S/ )-1-(2-(6-methylpyridin-3-yl)propan F
-2-yl)pyrrolidin-3-yl)propan-2-yl)car bamate isopropyl (R or iPrõ0 b¨t( F S)-(difluoro(3-(2-(5-fluorothiophen-HN F
220 / I 2-yl)ethyl)-1-(2-(6-methylpyridin-3-N s F
yl)propan-2-yl)pyrrolidin-3-yl)meth yl)carbamate isopropyl (1,2,2,2-tetrafluoro-1-((R
Pr _0 or \(:)-1\.iN / F

S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)carbamat isopropyl (R or 1PR h0 HN CF3 S)-(1,1,1,3,3,3-hexafluoro-2-(3-(2-(5 222 / I -fluorothiophen-2-yl)ethyl)-1-(2-(6-N s F
methylpyridin-3-yl)propan-2-yl)pyrr olidin-3-yl)propan-2-yl)carbamate phenyl ((R)-1-((R or Ph, 0 HN S)-3-(2-(5-fluorothiophen-2-yl)ethyl 223 / I )-1-(2-(6-methylpyridin-3-yl)propan N s F
-2-yl)pyrrolidin-3-yl)ethyl)carbamat Ph 0 phenyl ((S)-1-((R or 224 / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N s F
ic;
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)carbamat phenyl ((R)-fluoro((R or ,9 0-4( F
HN S)-3-(2-(5-fluorothiophen-2-yl)ethyl 225 / I )-1-(2-(6-methylpyridin-3-yl)propan N F
-2-yl)pyrrolidin-3-yl)methyl)carbam ate phenyl ((S)-fluoro((R or Ph ;
b1N4 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 226 ) )-1-(2-(6-methylpyridin-3-yl)propan N S F
MO -2-yl)pyrrolidin-3-yl)methyl)carbam ate phenyl ((S)-2,2,2-trifluoro-1-((R or ;
0-1( ,CF
HN 3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 227 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl)carbamat phenyl ((R)-2,2,2-trifluoro-1-4R or Ph 0 so/N CF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 228 \¨C1 N S F )-1-(2-(6-methylpyridin-3-yl)propan 121 -2-yl)pyrrolidin-3-yl)ethyl)carbamat phenyl (R or Ph 0 bINH3C CH3 S)-(2-(3-(2-(5-fluorothiophen-2-yl)et N S F hyl)-1-(2-(6-methylpyridin-3-yl)pro Th0 pan-2-yl)pyrrolidin-3-yl)propan-2-y1 )carbamate phenyl (1-fluoro-1-((R or Ph 0 b4H3C F S)-3-(2-(5-fluorothiophen-2-yl)ethyl HN-1s230 )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl)carbamat phenyl (1,1,1-trifluoro-2-((R or Ph 0 bl<H3C
HN CF3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 231 / I N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)propan-2-yl)car bamate phenyl (R or Ph 0 '04 F S)-(difluoro(3-(2-(5-fluorothiophen-HN¨F
232 2-yl)ethyl)-1-(2-(6-methylpyridin-3-N S F
yl)propan-2-yl)pyrrolidin-3-yl)meth yl)carbamate phenyl (1,2,2,2-tetrafluoro-1-((R or Ph 0 '04 F S)-3-(2-(5-fluorothiophen-2-yl)ethyl FIN¨cF3 233 )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl)carbamat phenyl (R or Ph 0 b4F3C
HN CF3 S)-(1,1,1,3,3,3-hexafluoro-2-(3-(2-(5 234 N / I F -fluorothiophen-2-yl)ethyl)-1-(2-(6-S
methylpyridin-3-yl)propan-2-yl)pyrr olidin-3-yl)propan-2-yl)carbamate 235 (R or H2N/N:
S)-1-((3-(2-(5-fluorothiophen-2-yl)et N s citrate F
hyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)gua nidine citrate (S or H2N-fN

N S F R)-1-((3-(2-(5-fluorothiophen-2-yl)e thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)urea 1-((R)-1-((R or D .
HN¨\1 237 CY\ ON S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-((S)-1-((R or 238 HN S)-3-(2-(5-fluorothiophen-2-yl)ethyl / I
N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-((R)-fluoro((R or C) F
2 239 HN / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)urea H2N- 1-((S)-fluoro((R or 240 FfN F /
S)-3-(2-(5-fluorothiophen-2-yl)ethyl I
N S F
Thn )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)urea 1-((S)-2,2,2-trifluoro-1-((R or C) / I
S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea H2N¨ fN CF3 / I
1-((R)-2,2,2-trifluoro-1-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea (R or u2N-fNS)-1-(2-(3-(2-(5-fluorothiophen-2-y1 243 / I )ethyl)-1-(2-(6-methylpyridin-3-yl)p N S F
ropan-2-yl)pyrrolidin-3-yl)propan-2-N
yl)urea 1-(1-fluoro-1-((R or H
244 2N¨FfN
S)-3-(2-(5-fluorothiophen-2-yl)ethyl / I
N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-(1,1,1-trifluoro-2-((Ror H2N¨fNCHF S)-3-(2-(5-fluorothiophen-2-yl)ethyl 245 / I N )-1-(2-(6-methylpyridin-3-yl)propan S
-2-yl)pyrrolidin-3-yl)propan-2-yl)ur ea (R or H2N¨fN F F S)-1-(difluoro(3-(2-(5-fluorothiophe N S F n-2-yl)ethyl)-1-(2-(6-methylpyridin-3-yl)propan-2-yl)pyrrolidin-3-yl)met hyl)urea (R or u2N¨fN cF3u3 S)-1-(1,1,1,3,3,3-hexafluoro-2-(3-(2-247 / I (5-fluorothiophen-2-yl)ethyl)-1-(2-( N S F
6-methylpyridin-3-yl)propan-2-yl)py rrolidin-3-yl)propan-2-yl)urea 1-((R)-1-((R or HN¨'K S)-3-(2-(5-fluorothiophen-2-yl)ethyl 248 ) N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)-3-isopro pylurea 1-((S)-1-((R or iPr, 0 HN1N_( S)-3-(2-(5-fluorothiophen-2-yl)ethyl 249 \¨es- )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)-3-isopro pylurea 1-((R)-fluoro((R or iPr, 0 S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)-3-isopr opylurea 1-((S)-fluoro((R or iPrx 0 HN¨ht F S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)-3-isopr opylurea 1-isopropy1-3-((S)-2,2,2-trifluoro-1-( iPr, 0 CF
HN 3 (R or 252 / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-isopropy1-3-((R)-2,2,2-trifluoro-1-IPr O
IIN N CF3 ((R or 253 / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea Prx 0 C% 3 (R or 254 ( S)-1-(2-(3-(2-(5-fluorothiophen-2-y1 I
N S F
)ethyl)-1-(2-(6-methylpyridin-3-yl)p ropan-2-yl)pyrrolidin-3-yl)propan-2-y1)-3-isopropylurea 1-(1-fluoro-1-((R or Pr 0 CH
S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan S
-2-yl)pyrrolidin-3-yl)ethyl)-3-isopro pylurea 1-isopropy1-3-(1,1,1-trifluoro-2-((R
iPr p or HN-4( CH, S)-3-(2-(5-fluorothiophen-2-yl)ethyl / I
N s F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)propan-2-yl)ur ea (R or Pr, 0 S)-1-(difluoro(3-(2-(5-fluorothiophe 257 / I n-2-yl)ethyl)-1-(2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyrrolidin-3-yl)met hyl)-3-isopropylurea (R or S)-1-(1,1,1,3,3,3-hexafluoro-2-(3-(2-N S F (5-flu0r0thi0phen-2-y1)ethy1)-1-(2-( 6-methylpyridin-3-yl)propan-2-yl)py rrolidin-3-yl)propan-2-y1)-3-isoprop ylurea 1-((R)-1-((R or Ph, 0 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 259 HN / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl)-3-phenyl urea 1-((S)-1-((R or Ph 0 41 _( S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)-3-phenyl urea 1-((R)-fluoro((R or Ph 0 HsN S)-3-(2-(5-fluorothiophen-2-yl)ethyl 261 HN / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)methyl)-3-phen ylurea 1-((S)-fluoro((R or Ph 0 HsN F S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)methyl)-3-phen ylurea 1-pheny1-3-((S)-2,2,2-trifluoro-1-((R
Ph b0 41¨' pF3 HN ' or 263 / I S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S F
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea 1-pheny1-3-((R)-2,2,2-trifluoro-1-(( Ph 0 1-1'N¨Ft CF3 Ror 264 F S)-3-(2-(5-fluorothiophen-2-yl)ethyl N S
)-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)ethyl)urea Ph 0 4111 CH3 (R or CH3 265 S)-1-(2-(3-(2-(5-fluorothiophen-2-y1 / I
N s F
)ethyl)-1-(2-(6-methylpyridin-3-yl)p ¨r ropan-2-yl)pyrrolidin-3-yl)propan-2-y1)-3-phenylurea 1-(1-fluoro-1-((R or Ph 0 1-1\1-1iN
S)-3-(2-(5-fluorothiophen-2-yl)ethyl 266 / I )-1-(2-(6-methylpyridin-3-yl)propan N S F
-2-yl)pyrrolidin-3-yl)ethyl)-3-phenyl urea 1-pheny1-3-(1,1,1-trifluoro-2-((R or Ph 0 CH3 S)-3-(2-(5-fluorothiophen-2-yl)ethyl 267 HN¨CF3 \¨esi )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-yl)propan-2-yl)ur ea (R or Ph 0 HµN F
S)-1-(difluoro(3-(2-(5-fluorothiophe N SF n-2-yl)ethyl)-1-(2-(6-methylpyridin-3-yl)propan-2-yl)pyrrolidin-3-yl)met hyl)-3-phenylurea (R or Ph 0 HIVIN CF3u3 S)-1-(1,1,1,3,3,3-hexafluoro-2-(3-(2-(5-fluorothiophen-2-yl)ethyl)-1-(2-( / I
N S F
6-methylpyridin-3-yl)propan-2-yl)py rrolidin-3-yl)propan-2-y1)-3-phenylu rea 270 (R or S)-1-(4-fluoropheny1)-3-43-(2-(5-flu HN¨f:
orothiophen-2-yl)ethyl)-1-(2-(6-met N S F
ctrate hylpyridin-3-yl)propan-2-yl)pyrrolid in-3-yl)methyl)guanidine citrate (R or 04FF S)-5-(2-(3-(ethoxydifluoromethyl)-3 271 N SF -(2-(5-fluorothiophen-2-yl)ethyl)pyr rolidin-l-yl)propan-2-y1)-2-methylp yridine (R or ¨\o¨\ HN-1() S)-4-(2-(3-(ethoxymethyl)-1-(2-(6-m 272 N) \-6NH
ethylpyridin-3-yl)propan-2-yl)pyrrol S
idin-3-yl)ethyl)-1H-thieno113,4-dlimi dazol-2(3H)-one (R or ___________________ Nr-,NH S)-4-(2-(3-(ethoxymethyl)-1-(2-(6-m \
273 N s ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethyl)-1H-thieno113,4-dlimi dazole (R or 0¨\ S)-4-(2-(3-(ethoxymethyl)-1-(2-(6-m ) 274 N s ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethy1)-1-methyl-1H-thienol 3,4-dlimidazole (R or S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m / I
275 N S N ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethyl)-1H-thienol2,3-dlimi dazole (R or /
S)-5-(2-(3-(ethoxymethyl)-1-(2-(6-m I

ethylpyridin-3-yl)propan-2-yl)pyrrol idin-3-yl)ethy1)-1-methyl-1H-thienol 2,3-dlimidazole (S)-4-((R or 1\I
S)-3-(2-(5-fluorothiophen-2-yl)ethyl 277 HF )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-y1)-3,4-dihydroqu inazolin-2(1H)-one (R)-4-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl o FAIN

S F )-1-(2-(6-methylpyridin-3-yl)propan -2-yl)pyrrolidin-3-y1)-3,4-dihydroqu inazolin-2(1H)-one (R or N
zNA__\ S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 279 )ethyl)-3-(4-methy1-4H-1,2,4-triazol -3-yl)pyrrolidin-1-yl)propan-2-y1)-2-..I N
methylpyridine 280 (S or F
R)-5-(2-(3-(5-(4-fluoropheny1)-1H-i midazol-2-y1)-3-(2-(5-fluorothiophe N s F
n-2-yl)ethyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine citrate 281 (S or F
R)-6-fluoro-2-(3-(2-(5-fluorothiophe HN
I n-2-yl)ethyl)-1-(2-(6-methylpyridin-N S F
¨icitrate 3-yl)propan-2-yl)pyrrolidin-3-y1)-1H
-benzo[d]imidazo1e citrate 282 ÇN (S or HN
I R)-5-(2-(3-(5-(tert-buty1)-1H-imidaz N S
:itrate ol-2-y1)-3-(2-(5-fluorothiophen-2-y1) ethyl)pyrrolidin-l-yl)propan-2-y1)-2-methylpyridine citrate 5-(2-((R or S)-3-((R)-6,7-difluoroisochroman-1-o 283 / y1)-3-(2-(5-fluorothiophen-2-yl)ethyl I
S F
)pyrrolidin-l-yl)propan-2-y1)-2-meth ylpyridine F F 5-(2-((R or S)-3-((R)-6,7-difluoroisochroman-3-o 284 / y1)-3-(2-(5-fluorothiophen-2-yl)ethyl I
N s F )pyrrolidin-l-yl)propan-2-y1)-2-meth ylpyridine (R or S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 esi )ethyl)-3-(isobutoxymethyl)pyrrolidi n-l-yl)propan-2-y1)-2-methylpyridin (S or R)-1-(4-fluoropheny1)-3-43-(2-(5-fl s uorothiophen-2-yl)ethyl)-1-(2-(6-me OH:r thylpyridin-3-yl)propan-2-yl)pyrroli din-3-yl)methyl)urea (S or cl R)-1-(4-chloropheny1)-3-43-(2-(5-fl s F uorothiophen-2-yl)ethyl)-1-(2-(6-me thylpyridin-3-yl)propan-2-yl)pyrroli din-3-yl)methyl)urea (S or F"'¶Nik R)-1-(3,4-difluoropheny1)-3-43-(24 s F 5-fluorothiophen-2-yl)ethyl)-1-(2-(6 -methylpyridin-3-yl)propan-2-yl)pyr rolidin-3-yl)methyl)urea (S or NI 0 R)-1-(5-fluoropyridin-2-y1)-3-((3-(2-NA
289 H / \
s F (5-fluorothiophen-2-yl)ethyl)-1-(2-( \ 6-methylpyridin-3-yl)propan-2-yl)py rrolidin-3-yl)methyl)urea 5-(2-((R or \
o S)-3-(ethoxy(pyridin-3-yl)methyl)-3 290 ( -(2-(5-fluorothiophen-2-yl)ethyl)pyr N
S F
rolidin-l-yl)butan-2-y1)-2-methylpyr idine (S or 01¨\ R)-5-(2-(3-(2-(5-fluorothiophen-2-y1 291 ) N S F )ethyl)-3-(piperidin-1-ylmethyl)pyrr olidin-l-yl)propan-2-y1)-2-methylpy ridine (S or HN N R)-1-((3-(2-(5-fluorothiophen-2-yl)e / I
292 N S F thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)pipe razine (S or / 293 R)-1-((3-(2-(5-fluorothiophen-2-yl)e thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)-4-i sopropylpiperazine (R or ( (DNI
S)-1-((3-(2-(5-fluorothiophen-2-yl)et 294 01 F hyl)-1-(2-(6-methylpyridin-3-yl)pro S
pan-2-yl)pyrrolidin-3-yl)methyl)pipe ridin-2-one (R or 0 N S)-4-(2-(3-(2-(5-fluorothiophen-2-y1 / I
295 N SF )ethyl)-1-(2-(6-methylpyridin-3-yl)p ropan-2-yl)pyrrolidin-3-yl)propan-2-yl)morpholine (S or HN N R)-1-((3-(2-(5-fluorothiophen-2-yl)e / I
296 N s F thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)-3,3 -dimethylpiperazine ¨\0 5-(2-(3-(ethoxymethyl)-3-(2-(5-fluor / I othiophen-2-y1)-2-methylpropyl)pyrr olidin-1-yl)propan-2-y1)-2-methylpy ridine ¨\0¨\ 5-(2-(3-(2,2-difluoro-2-(5-fluorothio )F)¨e phen-2-yl)ethyl)-3-(ethoxymethyl)p N F
yrrolidin-l-yl)propan-2-y1)-2-methyl pyridine - 0A__\
s F 5-(2-(3-(ethoxymethyl)-3-(2-(5-fluor 299 othiophen-2-yl)propyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine \ 5-(2-(3-(ethoxymethyl)-3-(2-fluoro--/ I 2-(5-fluorothiophen-2-yl)ethyl)pyrro lidin-l-yl)propan-2-y1)-2-methylpyri dine 5-(2-(3-(ethoxymethyl)-4,4-difluoro-3-(2-(5-fluorothiophen-2-yl)ethyl)py rrolidin-1-yl)propan-2-y1)-2-methylp yridine 5-(2-(3-(ethoxymethyl)-3-(2-(5-fluor I \ F
302 othiophen-2-yl)ethyl)-4,4-dimethylp yrrolidin-l-yl)propan-2-y1)-2-methyl , pyridine 5-(2-(3-(ethoxymethyl)-4-fluoro-3-( 303 I \ F
2-(5-fluorothiophen-2-yl)ethyl)pyrro lidin-l-yl)propan-2-y1)-2-methylpyri , dine 5-(2-(3-(ethoxymethyl)-3-(2-(5-fluor I s\ 304 F
othiophen-2-yl)ethyl)-4-methylpyrro lidin-l-yl)propan-2-y1)-2-methylpyri , dine 5-(2-(4-(ethoxymethyl)-4-(2-(5-fluor s\ F othiophen-2-yl)ethyl)-2,2-dimethylp yrrolidin-l-yl)propan-2-y1)-2-methyl , pyridine 5-(2-(4-(ethoxymethyl)-2,2-difluoro-306 F I \ F
4-(2-(5-fluorothiophen-2-yl)ethyl)py rrolidin-1-yl)propan-2-y1)-2-methylp I , yridine 5-(2-(4-(ethoxymethyl)-4-(2-(5-fluor \ F
307 othiophen-2-yl)ethyl)-2-methylpyrro lidin-l-yl)propan-2-y1)-2-methylpyri dine 5-(2-(4-(ethoxymethyl)-2-fluoro-44 I \ F

2-(5-fluorothiophen-2-yl)ethyl)pyrro F N
lidin-l-yl)propan-2-y1)-2-methylpyri dine (S or I F R)-5-(2-(3-(2,2-difluorobuty1)-3-(24 309 5-fluorothiophen-2-yl)ethyl)pyrrolid in-l-yl)propan-2-y1)-2-methylpyridi ne (R or S)-5-(2-(3-((1,1-difluoroethoxy)met I s\ F
310 hyl)-3-(2-(5-fluorothiophen-2-yeeth - yl)pyrrolidin-1-yl)propan-2-y1)-2-me thylpyridine (R or (oF
I \ F S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 311 )ethyl)-3-((1,1,2,2-tetrafluoroethoxy 0--/ - )methyl)pyrrolidin-l-yl)propan-2-y1) -2-methylpyridine 5-(1-((R or I \ F

S)-3-(ethoxymethyl)-3-(2-(5-fluorot hiophen-2-yl)ethyl)pyrrolidin-1-y1)-N
1-fluoroethyl)-2-methylpyridine 313 (S or R)-N-((3-(2-(5-fluorothiophen-2-y1) o s F ethyl)-1-(2-(6-methylpyridin-3-yl)pr atrate opan-2-yl)pyrrolidin-3-yl)methyl)me thanesulfonamide citrate (S or R)-4-fluoro-N-((3-(2-(5-fluorothioph eSc 314 F en-2-yl)ethyl)-1-(2-(6-methylpyridin s +0¨ -3-yl)propan-2-yl)pyrrolidin-3-yl)me thyl)benzenesulfonamide (S or F3C---\0 / R)-5-(2-(3-(2-(5-fluorothiophen-2-y1 \
F
315 )ethyl)-3-((2,2,2-trifluoroethoxy)met hyl)pyrrolidin-l-yl)propan-2-y1)-2-methylpyridine (S or 0õ0 R)-N-((3-(2-(5-fluorothiophen-2-y1) ysc 316 H s F
ethyl)-1-(2-(6-methylpyridin-3-yl)pr +0¨

opan-2-yl)pyrrolidin-3-yl)methyl)pr opane-2-sulfonamide (S or H2N / \ R)-2-(3-(2-(5-fluorothiophen-2-yl)et s F
317 hyl)-1-(2-(6-methylpyridin-3-yl)pro +0, pan-2-yl)pyrrolidin-3-yl)propan-2-a mine (S or 0õ0 R)-N-(2-(3-(2-(5-fluorothiophen-2-y 318 s F
Dethyl)-1-(2-(6-methylpyridin-3-y1) propan-2-yl)pyrrolidin-3-yl)propan-2-yl)methanesulfonamide 319 N-((R & S)-((S or \-c) -s- ¨N R)-3-(2-(5-fluorothiophen-2-yl)ethyl H`N
)-1-(2-(6-methylpyridin-3-yl)propan citrate -2-yl)pyrrolidin-3-y1)(pyridin-2-yl)m ethyl)methanesulfonamide citrate 320 (S or o=s R)-N-((3-(2-(5-fluorothiophen-2-y1) 41¨\
) N S F ethyl)-1-(2-(6-methylpyridin-3-yl)pr citrate opan-2-yl)pyrrolidin-3-yl)methyl)pr opane-2-sulfonamide citrate 321 N-((R & S)-((S or R)-3-(2-(5-fluorothiophen-2-yl)ethyl ¨N )-1-(2-(6-methylpyridin-3-yl)propan I
N s F -2-yl)pyrrolidin-3-y1)(pyridin-2-yl)m citrate ethyl)-4-methylbenzenesulfonamide citrate 322 (S or HR
.S' R)-((3-(2-(5-fluorothiophen-2-yl)eth 0-Hsrµi / I y1)-1-(2-(6-methylpyridin-3-yl)propa N S
citrate n-2-yl)pyrrolidin-3-yl)methyl)sulfa mic acid citrate (S or R)-N-(2-(3-(2-(5-fluorothiophen-2-y 323 s F Dethyl)-1-(2-(6-methylpyridin-3-y1) propan-2-yl)pyrrolidin-3-yl)propan-N
2-yl)acetamide (S or 0_0 R)-N-(2-(3-(2-(5-fluorothiophen-2-y ss, 324 s F Dethyl)-1-(2-(6-methylpyridin-3-y1) propan-2-yl)pyrrolidin-3-yl)propan-2-yl)benzenesulfonamide (R or S)-1-((3-(2-(5-fluorothiophen-2-yl)et 325 F hyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)gua nidine (R or NH S)-1-(4-fluoropheny1)-3-43-(2-(5-flu = N
326 HHForothiophen-2-yl)ethyl)-1-(2-(6-met -} hylpyridin-3-yl)propan-2-yl)pyrrolid in-3-yl)methyl)guanidine (R or 0õ0 H2N=s S)-2-(3-(2-(5-fluorothiophen-2-yl)et ;
/

S F hyl)-1-(2-(6-methylpyridin-3-yl)pro +0¨:( pan-2-yl)pyrrolidin-3-yl)propan-2-y1 sulfamoylamine (R or oo S)-((3-(2-(5-fluorothiophen-2-yl)eth /
328 s F y1)-1-(2-(6-methylpyridin-3-yl)propa N1)-n-2-yl)pyrrolidin-3-yl)methyl)sulfa moyl propan-2-yl-amine (R or F 14111 0,s,?
329 S)-((3-(2-(5-fluorothiophen-2-yl)eth N-1-- 0¨ y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidin-3-yl)methyl)sulfa moyl 4-fluorophenylamine (S or r/N R)-5-(2-(3-(1-(tert-buty1)-1H-imidaz 330 ol-2-y1)-3-(2-(5-fluorothiophen-2-y1) ethyl)pyrrolidin-l-yl)propan-2-y1)-2-..I
methylpyridine (S or R)-5-(2-(3-(5-(tert-buty1)-1H-imidaz HN
331 / I ol-2-y1)-3-(2-(5-fluorothiophen-2-y1) S"--"F
ethyl)pyrrolidin-l-yl)propan-2-y1)-2-N
methylpyridine F (S or R)-6-fluoro-2-(3-(2-(5-fluorothiophe HN
332 / I n-2-yl)ethyl)-1-(2-(6-methylpyridin-N S F
3-yl)propan-2-yl)pyrrolidin-3-y1)-1H
-benzoldlimidazole
2. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
5-((R or 0 S)-3-(ethoxymethyl)-3-(2-(5-methylt 1 N hiophen-2-yl)ethyl)pyrrolidin-1-y1)-2-methy1-6,7-dihydro-5H-cyclopenta lblpyridine (S or R)-3-(2-(3-(ethoxymethyl)-3-(2-(3-methylthiophen-2-yl)ethyl)pyrrolidin -1-yl)propan-2-yl)pyridine Tho (S or R)-3-(2-(3-(ethoxymethyl)-3-(2-(thio phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-yl)pyridine (S or R)-5-(2-(3-(2-ethoxypropan-2-y1)-3-4 (2-(thiophen-2-yl)ethyl)pyrrolidin-1-yl)propan-2-y1)-2-methylpyridine citrate N citrate 5-(24(S&R)-3-((S or R)-1-ethoxyethyl)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-yepropan-2-y1) -2-methylpyridine citrate citrate 2-methy1-5-(24(3R or 0 6 S)-3-phenethy1-3-(tetrahydrofuran-2-yl)pyrrolidin-l-yl)propan-2-yl)pyridi citrate ne citrate 5-(2-((3R or I \ S)-3-(tetrahydrofuran-2-y1)-3-(2-(thi 7 ophen-2-yl)ethyl)pyrrolidin-1-y1)pro 12)_0_ cF3 pan-2-y1)-2-(trifluoromethyl)pyridin c() 2-methy1-5-(24(R or S)-3-((S or R)-tetrahydrofuran-2-y1)-3-(2-(thiop 8 hen-2-yl)ethyl)pyrrolidin-1-y1)propa n-2-yl)pyridine
3. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp Structure Name ound No.
2-methy1-5-(24(3S or r R)-3-(tetrahydrofuran-2-y1)-3-(thiop 9 s hen-2-ylmethyl)pyrrolidin-1-yl)prop an-2-yl)pyridine 5-(2-((R or S)-3-((S or R)-ethoxy(phenyl)methyl)-3-(2-(thio /
phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-y1)-2-methylpyridine o 5-(2-((R or S)-3-((R or S)-ethoxy(phenyl)methyl)-3-(2-(thio phen-2-yl)ethyl)pyrrolidin-1-y1)prop an-2-y1)-2-methylpyridine 0A_\
5-(2-((R or S)-3-((R or S)-1-ethoxyethyl)-3-(2-(thiophen-2-12 S"
yl)ethyl)pyrrolidin-1-yepropan-2-y1) -2-methylpyridine citrate 1\1 citrate 05_\
5-(2-((R or S)-3-((S or R)-1-ethoxyethyl)-3-(2-(thiophen-2-13 S"
yl)ethyl)pyrrolidin-1-yepropan-2-y1) -2-methylpyridine citrate citrate (R or 14 S)-2-methy1-5-(2-(3-(propoxymethyl )-3-(2-(thiophen-2-yl)ethyl)pyrrolidi n-l-yl)propan-2-yl)pyridinecitrate citrate ( (R or N = S)-1-((3-(ethoxymethyl)-1-(2-(6-met 15 hylpyridin-3-yl)propan-2-yl)pyrrolid 1\1) citrate in-3-yl)methy1)-3-ethyl-1,3-dihydro-N 2H-benzoldlimidazol-2-one citrate MF (R or03C CF3 S \
s S)-5-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex 16 N afluoropropan-2-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-y1)propan-2-N yl)-2-methylpyridine ---f3C C F3 ' , 5-(2-((R or o \
S)-3-(2-ethoxy-1,1,1,3,3,3-hexafluor 17 N opropan-2-y1)-3-(2-(thiophen-2-yl)et I hyl)pyrrolidin-1-yebutan-2-y1)-2-me r\l thylpyridinecitrate
4. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
(R or _\ 0 iii.6 o¨ 7 WI S)-1-((3-(ethoxymethyl)-1-(2-(6-met 4.N hylpyridin-3-yl)propan-2-yl)pyrrolid citrate N in-3-yemethyl)-1,3-dihydro-2H-ben zoldlimidazol-2-one citrate 0 2-methy1-5-(24(3R or S)-3-(tetrahydrofuran-2-y1)-3-(3-(thi s /
/ X ophen-2-yl)propyl)pyrrolidin-1-yl)pr ¨N opan-2-yl)pyridine --\
0 (R or 20 s / S)-5-(2-(3-(ethoxymethyl)-3-(3-(thio / \ phen-2-yl)propyl)pyrrolidin-1-yl)pro ¨N pan-2-y1)-2-methylpyridine o¨\ (R or S)-5-(2-(3-(isopropoxymethyl)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-y1) propan-2-y1)-2-methylpyridine 22 N) S S)-3-(isopropoxymethyl)-3-(2-(thiop hen-2-yl)ethyl)pyrrolidin-1-yl)butan-2-y1)-2-methylpyridine (R or () ¨\0¨\N * F S)-1-((3-(ethoxymethyl)-1-(2-(6-met 23 N) citrate hylpyridin-3-yl)propan-2-yl)pyrrolid in-3-yl)methyl)-3-ethyl-5-fluoro-1,3--1;dihydro-2H-benzoldlimidazol-2-one citrate N ;N
(R or S)-2-methy1-5-(1-(2-(6-methylpyridi 24 / I n-3-yl)propan-2-y1)-3-(2-(thiophen-2 -yl)ethyl)pyrrolidin-3-y1)-1,3,4-thiad citrate iazole citrate (R or S)-5-(2-(3-(ethoxymethyl)-3-(2-(5-fl 25 uorobenzolblthiophen-2-yl)ethyl)pyr citrate rolidin-1-yl)propan-2-y1)-2-methylp yridine citrate 0 (S or , 26 R)-5-(2-(3-(ethoxymethy1)-3-(thioph citrate en-2-ylmethyl)pyrrolidin-1-yl)propa n-2-y1)-2-methylpyridine citrate
5. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.

¨\() (R or S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m 0 \¨cfNi ethylpyridin-3-yl)propan-2-yl)pyrrol ¨I. citrate idin-3-yl)ethyl)thieno113,2-blpyridine N citrate ¨\ (R or o S)-2-(2-(3-(ethoxymethyl)-1-(2-(6-m / I
28 N S N ethylpyridin-3-yl)propan-2-yl)pyrrol ¨0..... citrate idin-3-yl)ethyl)thieno112,3-61pyridine N citrate (S &
5...... ----, R)-1-(2-(3-(ethoxymethyl)-1-(2-(6-29 Q * methylpyridin-3-yl)propan-2-yl)pyrr olidin-3-yl)ethyl)-3-ethyl-1,3-dihydr Thn N o-2H-benzo11dflimidazol-2-one (R or S S)-5-(2-(3-(ethoxymethyl)-3-(2-(5-(t 30 N rifluoromethyl)thiophen-2-yl)ethyl)p citrate yrrolidin-1-yl)propan-2-y1)-2-methyl N pyridine citrate CI (R or F S)-5-(2-(3-(2-(4-chloro-5-fluorothio s 31 phen-2-yl)ethyl)-3-(ethoxymethyl)py N
..,..k.õ.7õ..z,* citrate rrolidin-l-yl)propan-2-y1)-2-methylp fl'7 yridine citrate ci (R or s S)-5-(2-(3-(2-(4-chlorothiophen-3-y1 N
)ethy )-3-(ethox meth 1 1 rrolidin-1 Y 3' )py -----, I -yl)propan-2-y1)-2-methylpyridine N
CI
(R or s S)-5-(2-(3-(2-(4-chlorothiophen-2-y1 33 N )ethyl)-3-(ethoxymethyl)pyrrolidin-1 -yl)propan-2-y1)-2-methylpyridine N
CF3 5-(2-((R & S)-3-((S or .--\
I \ F
0 S R)-1-ethoxy-2,2,2-trifluoroethyl)-3-( N 2-(5-fluorothiophen-2-yl)ethyl)pyrro --"
--1-0 lidin-1-yl)propan-2-y1)-2-methylpyri -----N dine ¨\
0 5-(2-((R or S)-3-((S or / I R)-1-ethoxyethyl)-3-(2-(5-fluorothio citrate phen-2-yl)ethyl)pyrrolidin-1-y1)prop ma, N an-2-y1)-2-methylpyridine citrate
6. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
------N cF3 b_cF, (R or \
S)-5-(2-(3-(2-ethoxy-1,1,1,3,3,3-hex N
36 S"--F afluoropropan-2-y1)-3-(2-(5-fluoroth ¨, iophen-2-yl)ethyl)pyrrolidin-1-y1)pr N opan-2-y1)-2-methylpyridine 5-(2-((R or S)-3-((R or el S'"--F S)-1-ethoxyethyl)-3-(2-(5-fluorothio phen-2-yl)ethyl)pyrrolidin-1-y1)prop 1 citrate an-2-y1)-2-methylpyridine citrate HN_ e (R or (:) S)-(3-(2-(5-fluorothiophen-2-yl)ethy 38 l I 1)-1-(2-(6-methylpyridin-3-yl)propan N S F
--0 citrate -2-yl)pyrrolidin-3-yl)methyl ,..., N isopropylcarbamate citrate HN-e (R or o 39 0 / I S)-(3-(2-(5-fluorothiophen-2-yl)ethy 1)-1-(2-(6-methylpyridin-3-yl)propan N S F
--Ti, citrate -2-yl)pyrrolidin-3-yl)methyl 1\1-- phenylcarbamate citrate iPr\ 0 isopropyl (S or o-Ft R)-((3-(2-(5-fluorothiophen-2-yl)eth 40 0 \-0, y1)-1-(2-(6-methylpyridin-3-yl)propa S F
citrate n-2-yl)pyrrolidin-3-yl)methyl)carba N mate citrate Ph 0 phenyl (S or b4 HN¨\ R)-((3-(2-(5-fluorothiophen-2-yl)eth 41 ) \¨el y1)-1-(2-(6-methylpyridin-3-yl)propa N S F
n-2-yl)pyrrolidin-3-yl)methyl)carba Th( N mate (S or R)- 1 -((3-(2-(5-fluorothiophen-2-yl)e 42 / thyl)-1-(2-(6-methylpyridin-3-yl)pro citrate pan-2-yepyrrolidin-3-yl)methyl)-34 sopropylurea citrate Ph 0 (S or 1-1'N¨Ft R)-1-((3-(2-(5-fluorothiophen-2-yl)e 43 / I thyl)-1-(2-(6-methylpyridin-3-yl)pro N S
citrate pan-2-yepyrrolidin-3-yl)methyl)-3-p henylurea citrate
7. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
44 HO (R or S)-(3-(4-fluorophenethyl)-1-(pyridin CC citrate -3-ylmethyl)pyrrolidin-3-yl)methano 1 citrate 0 (R or S)-3-43-(ethoxymethyl)-3-(4-fluoro phenethyl)pyrrolidin-1-yemethyl)-5-)-. -Fcitrate fluoropyridine citrate F_(F
(R or S)-5-(2-(3-((difluoromethoxy)methyl 82 / I )-3-(2-(thiophen-2-yl)ethyl)pyrrolidi n-1-yl)propan-2-y1)-2-methylpyridin citrate e citarte N
(R or N
S)-3-43-(ethoxymethyl)-1-(2-(6-met 83 hylpyridin-3-yl)propan-2-yl)pyrrolid citrate in-3-yemethy1)-3H-imidazol4,5-clp N = yridine citarte (R or F s)-1-((3-(ethoxymethyl)-1-(2-(6-met 84 o¨\
hylpyridin-3-yl)propan-2-yl)pyrrolid ) citrate in-3-yl)methyl)-3-ethyl-5,6-difluoro-N
1,3-dihydro-2H-benzo ldlimidazol-2-one citarte F_-N (R or S)-1-43-(ethoxymethyl)-1-(2-(6-met 85 hylpyridin-3-yl)propan-2-yl)pyrrolid citrate in-3-yemethyl)-1H-imidazol4,5-clp yridine citrate ) 5-(2-((S or R)-3-((R&
o S)-ethoxy(pyridin-2-yl)methyl)-3-(2-86 (thiophen-2-yl)ethyl)pyrrolidin-1-y1) propan-2-y1)-2-methylpyridine citrate citrate
8. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
5-(2-((R or S)-3-((S or R)-isochroman-l-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-yepropan-2-citrate yl)-2-methylpyridine citrate 5-(2-((R or S)-3-((R or S)-isochroman-1-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-yepropan-2-citrate yl)-2-methylpyridine citrate 5-(2-((R or S)-3-((S or R)-isochroman-l-y1)-3-(2-(thiophen-2-yl)ethyl)pyrrolidin-1-yebutan-2-y1 )-2-methylpyridine citrate citrate CF3 5-(2-((R or I \ 0 F S)-3-((S&R)-1-ethoxy-2,2,2-trifluor 90 oethyl)-3-(2-(5-fluorothiophen-2-y1) --N
ethyl)pyrrolidin-1-yl)butan-2-y1)-2----methylpyridine 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth 91 ylpyridin-3-yl)propan-2-yl)pyrrolidi n-3-yl)ethyl)-1H-imidazol4,5-clpyri citrate dine citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth ¨\O¨\ /¨N(Nhi ylpyridin-3-yl)propan-2-yl)pyrrolidi N
n-3-yl)ethyl)-1,3-dihydro-2H-imidaz citarte ol4,5-clpyridin-2-one citrate 5-(2-((R or F3c CF3 / \ 93 S)-3-(2-ethoxy-1,1,1,3,3,3-hexafluor S F
opropan-2-y1)-3-(2-(5-fluorothiophe n-2-yl)ethyl)pyrrolidin-1-y1)butan-2-N yl)-2-methylpyridine 5-(2-((R or S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-3-((R or S F S)-isochroman-l-yl)pyrrolidin-l-y1) ¨r citrate propan-2-y1)-2-methylpyridine citrate
9. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, , which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.

/ I
5-(2-((R or o S)-3-(2-(5-fluorothiophen-2-yl)ethyl )-3-((S or N S F R)-isochroman-l-yl)pyrrolidin-l-y1) ¨, propan-2-y1)-2-methylpyridine citrate &N citrate 5-(2-((R or S)-3-((R or s\ F S)-ethoxy(phenyl)methyl)-3-(2-(5-fl o 96 uorothiophen-2-yl)ethyl)pyrrolidin-1 N citrate -yl)butan-2-y1)-2-methylpyridine N¨\--O----- citrate N
5-(2-((R or S)-3-((R or ¨\o S)-ethoxy(phenyl)methyl)-3-(2-(5-fl uorothiophen-2-yl)ethyl)pyrrolidin-1 N S F -yl)propan-2-y1)-2-methylpyridine 1 citrate citrate N
5-(2-((R or S)-3-((S or ¨\o R)-ethoxy(phenyl)methyl)-3-(2-(5-fl 98 / I uorothiophen-2-yl)ethyl)pyrrolidin-1 N S F -yl)propan-2-y1)-2-methylpyridine -r citrate citrate N
3\-- 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth ¨\0¨\ rN
99 0 = ylpyridin-3-yl)propan-2-yl)pyrrolidi N
F F n-3-yl)ethyl)-5,6-difluoro-1,3-dihydr ¨I1),,, citrate o-2H-benzo[d]imidazo1-2-one citrate N
C' 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth Q *F ylpyridin-3-yl)propan-2-yl)pyrrolidi 100 n-3-yl)ethyl)-5,6-difluoro-3-isobutyl ¨XF citrate -1,3-dihydro-2H-benzo[d]imidazo1-2 N -one citrate 1-(2-(3-(ethoxymethyl)-1-(2-(6-meth N
¨`0 5.--N^
¨\ /¨
c) 40 F ylpyridin-3-yl)propan-2-yl)pyrrolidi 101 n-3-yl)ethyl)-3-ethyl-5,6-difluoro-1, F citrate 3-dihydro-2H-benzo[dlimidazol-2-o N ne citrate o (S)-4-((3-(ethoxymethyl)-3-(2-(thiop 102 hen-2-yl)ethyl)pyrrolidin-1-y1)methy Cì
H3PO4 1)pyridine H3PO4 salt
10. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
/ 5-(2-((R or 0 N S)-34(S&R)-ethoxy(pyridin-2-yl)me 103 / I thyl)-3-(2-(5-fluorothiophen-2-yl)eth N S F
yl)pyrrolidin-l-yl)propan-2-y1)-2-me Çj citrate thylpyridine citrate I F 5-(2-((R or S)-3-((S or R) -1-ethoxyethyl)-3-(2-(5-fluorothio 104 citrate phen-2-yl)ethyl)pyrrolidin-1-y1)buta \
n-2-y1)-2-methylpyridine citrate F 5-(2-((R or S)-3-((R or 105 S)-1-ethoxyethyl)-3-(2-(5-fluorothio ic trate phen-2-yl)ethyl)pyrrolidin-1-y1)buta n-2-y1)-2-methylpyridine citrate (S or 0 Ni)R)-4-((3-(2-(5-fluorothiophen-2-yl)e 106 N s thyl)-1-(2-(6-methylpyridin-3-yl)pro pan-2-yl)pyrrolidin-3-yl)methyl)mor Pholine 107 (S or PN R)-1-ethy1-3-43-(2-(5-fluorothiophe n-2-yl)ethyl)-1-(2-(6-methylpyridin-N S F 3-yl)propan-2-yl)pyrrolidin-3-yl)met cltrate hyl)-1,3-dihydro-2H-benzoldlimidaz ol-2-one citrate -----\ (R or o / \
s S)-5-(2-(3-(2-(4,5-dimethylthiophen-108 N 2-yl)ethyl)-3-(ethoxymethyl)pyrrolid ---.) citrate in-1-yepropan-2-y1)-2-methylpyridi tN ne citrate 0 (R or O'S= S)-N-((3-(2-(5-fluorothiophen-2-yl)e / \
109 il s F thyl)-1-(2-(6-methylpyridin-3-yl)pro N
citrate pan-2-yl)pyrrolidin-3-yl)methyl)met N
hanesulfonamide citrate (R or S)-N-((3-(2-(5-fluorothiophen-2-yl)e H
110 / \
s F thyl)-1-(2-(6-methylpyridin-3-yl)pro atrate pan-2-yl)pyrrolidin-3-yl)methyl)-4-methylbenzenesulfonamide citrate
11. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
111 (S or F)=\
R)-4-fluoro-N-((3-(2-(5-fluorothioph 0-Esi,--: en-2-yl)ethyl)-1-(2-(6-methylpyridin 5-\¨(3, -3-yl)propan-2-yl)pyrrolidin-3-yl)me N s F
'irate thyl)benzenesulfonamide citrate N
FN (S & R)-5-((R or O S)-3-(2-(5-fluorothiophen-2-yl)ethyl / \
112 s F )-1-(2-(6-methylpyridin-3-yl)propan-N
\ /citrate 2-yl)pyrrolidin-3-yl)oxazolidin-2-on N e citrate eN,N (R or HN ' \ __________________________ a, N S F S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 113 )ethyl)-3-(1H-imidazol-2-y1)pyrrolid ¨, in-1-yepropan-2-y1)-2-methylpyridi citrate ne citrate / (R or S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 114 \-ON )ethyl)-3-(1-methy1-1H-imidazol-2-y 1)pyrrolidin-1-yepropan-2-y1)-2-met hylpyridine citrate N (R or S)-5-(2-(3-(2-(5-fluorothiophen-2-y1 115 S--N )ethyl)-3-(4H-1,2,4-triazol-3-y1)pyrr F
olidin-l-yl)propan-2-y1)-2-methylpy ridine > ________________ \ (R or o¨\
S)-5-(2-(3-((cyclopropylmethoxy)me N) 116 thyl)-3-(2-(5-fluorothiophen-2-yl)eth s¨NF
yl)pyrrolidin-l-yl)propan-2-y1)-2-me ci=trate N thylpyridine citrate o (R or H2N \ S)-3-(2-(5-flu0r0thi0phen-2-y1)ethy1 s F
117 )-1-(2-(6-methylpyridin-3-yl)propan-2-yl)pyrrolidine-3-carboxamide citrate N citrate .o (R or I s\ F
S,E)-3-(2-(5-fluorothiophen-2-yl)eth 118 y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidine-3-carbaldehyde 0-methyl oxime citrate citrate
12. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.

0-5ro (S or R)-((3-(2-(5-fluorothiophen-2-yl)eth 119 S y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidin-3-yl)methyl)sulfam oyl amine 120 F121\1 c)_) (S or R)-o'HN ((3-(2-(5-fluoro-thiophen-2-yl)ethyl) \¨esiF -1-(2-(6-methylpyridin-3-yl)propan-citrate 2-yl)pyrrolidin-3-y1)(pyridin-2-yem ethyl)sulfamoyl amine 121 NN, (S or R)-0+0 ((3-(2-(5-fluorothiophen-2-yeethyl)-HN, s\ F 1-(2-(6-methylpyridin-3-yl)propan-2 -yl)pyrrolidin-3-yl)methyl)sulfamoyl dimethyl amine 4111 (R or S)-((3-(2-(5-fluorothiophen-2-yl)eth 0-,1=0 y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidin-3-yl)methyl)sulfam citrate oyl 4-fluorophenylamine citrate 123 (R or S)-((3-(2-(5-fluorothiophen-2-yl)eth HN y1)-1-(2-(6-methylpyridin-3-yl)propa o'H'N n-2-yl)pyrrolidin-3-yl)methyl)sulfam / I
N S oyl 4-methylphenyl amine ¨icitrate 124 CI (R or S)-((3-(2-(5-fluorothiophen-2-yl)eth CI
y1)-1-(2-(6-methylpyridin-3-yl)propa HN
n-2-yl)pyrrolidin-3-yl)methyl)sulfam / I
N S F oyl 2,4-dichloro phenyl amine Exact Mass. 584.12 tPSA: 73.8 CLogP: 6.67 125 (S or 40 R)-4-methyl-N-((1-(pyridin-3-ylmet o=y=o hyl)-3-(2-(thiophen-2-yl)ethyl)pyrrol HN idin-3-yl)methyl)benzenesulfonamid e citrate citrate 126 (S or R)-N-((3-(2-(4,5-dimethylthiophen-2 -yl)ethyl)-1-(2-(6-methylpyridin-3-y1 )propan-2-yl)pyrrolidin-3-yl)methyl) N s Lcitrate -4-methylbenzenesulfonamide citrate
13. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
127 (S or 40 R)-N-((3-(4-fluorophenethyl)-1-(2-( 01=0 6-methylpyridin-3-yl)propan-2-yl)py HN rrolidin-3-yl)methyl)-4-methylbenze nesulfonamide citrate citrate >r 235 NH (R or N2N¨FL
S)-1-((3-(2-(5-fluorothiophen-2-yl)et N F
hyl)-1-(2-(6-methylpyridin-3-yl)prop S
citrate an-2-yl)pyrrolidin-3-yl)methyl)guani dine citrate 270 (R or N: S)-1-(4-fluoropheny1)-3-43-(2-(5-flu HNI
orothiophen-2-yl)ethyl)-1-(2-(6-met N S F hylpyridin-3-yl)propan-2-yl)pyrrolid in-3-yl)methyl)guanidine citrate (S or R)-5-(2-(3-(5-(4-fluoropheny1)-1H-i N S F midazol-2-y1)-3-(2-(5-fluorothiophe n-2-yl)ethyl)pyrrolidin-1-y1)propan-2-y1)-2-methylpyridine citrate 281 F (S or R)-6-fluoro-2-(3-(2-(5-fluorothiophe HN n-2-yl)ethyl)-1-(2-(6-methylpyridin-/ I
N S F 3-yl)propan-2-yl)pyrrolidin-3-y1)-1H
¨****C-Xcitrate -benzoldlimidazole citrate N (S or HN R)-5-(2-(3-(5-(tert-buty1)-1H-imidaz / I ol-2-y1)-3-(2-(5-fluorothiophen-2-y1) N S F
- =îíiõc, !trate ethyl)pyrrolidin-1-yl)propan-2-y1)-2-N methylpyridine citrate 313 (S or OSN
/ R)-N-((3-(2-(5-fluorothiophen-2-yl)e s thyl)-1-(2-(6-methylpyridin-3-yl)pro atrate pan-2-yl)pyrrolidin-3-yl)methyl)met N hanesulfonamide citrate 319 / \ N-((R & S)-((S or -o -s- ¨N R)-3-(2-(5-fluorothiophen-2-yl)ethyl H`N
/ I )-1-(2-(6-methylpyridin-3-yl)propan-2-yl)pyrrolidin-3-y1)(pyridin-2-yl)m citrate ethyl)methanesulfonamide citrate
14. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
320 ¨(0 0=e, (S or HN R)-N-((3-(2-(5-fluorothiophen-2-yl)e / thyl)-1-(2-(6-methylpyridin-3-yl)pro N S F
pan-2-yl)pyrrolidin-3-yl)methyl)pro citrate pane-2-sulfonamide citrate 321 N-((R & S)-((S or R)-3-(2-(5-fluorothiophen-2-yl)ethyl )-1-(2-(6-methylpyridin-3-yl)propan-/ 2-yl)pyrrolidin-3-y1)(pyridin-2-yem N s F
citrate ethyl)-4-methylbenzenesulfonamide citrate 322 HO(S or F R)-((3-(2-(5-fluorothiophen-2-yl)eth / I y1)-1-(2-(6-methylpyridin-3-yl)propa N S
licitrate n-2-yl)pyrrolidin-3-yl)methyl)sulfam ic acid citrate _2( (S or R)-N-(2-(3-(2-(5-fluorothiophen-2-y 323 s F 1)ethyl)-1-(2-(6-methylpyridin-3-yl)p ropan-2-yepyrrolidin-3-yl)propan-2-yl)acetamide (S or 0, 0 / R)-N-(2-(3-(2-(5-fluorothiophen-2-y 324 S F 1)ethyl)-1-(2-(6-methylpyridin-3-yl)p ropan-2-yl)pyrrolidin-3-yl)propan-2-N
yl)benzenesulfonamide NH (R or H2N N S)-1-((3-(2-(5-fluorothiophen-2-yl)et 325 S F hyl)-1-(2-(6-methylpyridin-3-yl)prop an-2-yl)pyrrolidin-3-yl)methyl)guani dine (R or F NI, S)-1-(4-fluoropheny1)-3-43-(2-(5-flu 326 HS F orothiophen-2-yl)ethyl)-1-(2-(6-met hylpyridin-3-yl)propan-2-yl)pyrrolid in-3-yl)methyl)guanidine (R or 0õ0 H2NK S)-2-(3-(2-(5-fluorothiophen-2-yl)et /
327 s F
hyl)-1-(2-(6-methylpyridin-3-yl)prop an-2-yl)pyrrolidin-3-yl)propan-2-y1 sulfamoylamine
15. The following compounds of claim 1 or a pharmaceutically acceptable salt thereof, which demonstrated efficacy in an in vivo animal model for pain tolerance:
Comp ound Structure Name No.
(R or 'H S)-((3-(2-(5-fluorothiophen-2-yl)eth 328 s F y1)-1-(2-(6-methylpyridin-3-yl)propa n-2-yl)pyrrolidin-3-yl)methyl)sulfam oyl propan-2-yl-amine (R or F 4111 NO,sfN
S)-((3-(2-(5-fluorothiophen-2-yl)eth y1)-1 -(2- (6-methylpyridin-3 -yl)prop a n-2- yl)pyrrolidin-3 -yllmethylls ulfam oyl 4-fluorophenylamine (S or R)-5 -(2- (3- (1 - (tert-buty1)- 1H-imidaz ) ol-2- y1)-3- (2- (5 -fluorothiophen-2-y1) N
330 ethyl)pyrrolidin- 1- yl)propan-2-y1)-2-methylpyridine I
(S or HN R)-5 -(2- (3- (5 - (tert-buty1)- 1H-imidaz 331 / I ol-2- y1)-3- (2- (5 -fluorothiophen-2-y1) S F ethyl)pyrrolidin- 1- yl)propan-2-y1)-2-methylpyridine F
(S or HN R)-6-fluoro-2- (3 - (2-(5-fluorothiophe 332 / I n-2- yl)ethyl)- 1 -(2- (6-methylpyridin-S F 3- yl)prop an-2-yl)pyrrolidin-3 -y1)--benzoldlimidazole
16. One of compound Nos. 1-16 of claim 1 or a pharmaceutically acceptable salt thereof.
17. One of compound Nos. 18-44 of claim 1 or a pharmaceutically acceptable salt thereof.
18. One of compound Nos. 82-109 of claim 1 or a pharmaceutically acceptable salt thereof.
19. One of compound Nos. 111-123 of claim 1 or a pharmaceutically acceptable salt thereof.
20. One of compound Nos. 126; 127; 280-282;313 and 319-322 of claim 1 or a pharmaceutically acceptable salt thereof.
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